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1.  Neuroimaging for the Evaluation of Chronic Headaches 
Executive Summary
Objective
The objectives of this evidence based review are:
i) To determine the effectiveness of computed tomography (CT) and magnetic resonance imaging (MRI) scans in the evaluation of persons with a chronic headache and a normal neurological examination.
ii) To determine the comparative effectiveness of CT and MRI scans for detecting significant intracranial abnormalities in persons with chronic headache and a normal neurological exam.
iii) To determine the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Clinical Need: Condition and Target Population
Headaches disorders are generally classified as either primary or secondary with further sub-classifications into specific headache types. Primary headaches are those not caused by a disease or medical condition and include i) tension-type headache, ii) migraine, iii) cluster headache and, iv) other primary headaches, such as hemicrania continua and new daily persistent headache. Secondary headaches include those headaches caused by an underlying medical condition. While primary headaches disorders are far more frequent than secondary headache disorders, there is an urge to carry out neuroimaging studies (CT and/or MRI scans) out of fear of missing uncommon secondary causes and often to relieve patient anxiety.
Tension type headaches are the most common primary headache disorder and migraines are the most common severe primary headache disorder. Cluster headaches are a type of trigeminal autonomic cephalalgia and are less common than migraines and tension type headaches. Chronic headaches are defined as headaches present for at least 3 months and lasting greater than or equal to 15 days per month. The International Classification of Headache Disorders states that for most secondary headaches the characteristics of the headache are poorly described in the literature and for those headache disorders where it is well described there are few diagnostically important features.
The global prevalence of headache in general in the adult population is estimated at 46%, for tension-type headache it is 42% and 11% for migraine headache. The estimated prevalence of cluster headaches is 0.1% or 1 in 1000 persons. The prevalence of chronic daily headache is estimated at 3%.
Neuroimaging
Computed Tomography
Computed tomography (CT) is a medical imaging technique used to aid diagnosis and to guide interventional and therapeutic procedures. It allows rapid acquisition of high-resolution three-dimensional images, providing radiologists and other physicians with cross-sectional views of a person’s anatomy. CT scanning poses risk of radiation exposure. The radiation exposure from a conventional CT scanner may emit effective doses of 2-4mSv for a typical head CT.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used to aid diagnosis but unlike CT it does not use ionizing radiation. Instead, it uses a strong magnetic field to image a person’s anatomy. Compared to CT, MRI can provide increased contrast between the soft tissues of the body. Because of the persistent magnetic field, extra care is required in the magnetic resonance environment to ensure that injury or harm does not come to any personnel while in the environment.
Research Questions
What is the effectiveness of CT and MRI scanning in the evaluation of persons with a chronic headache and a normal neurological examination?
What is the comparative effectiveness of CT and MRI scanning for detecting significant intracranial abnormality in persons with chronic headache and a normal neurological exam?
What is the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Research Methods
Literature Search
Search Strategy
A literature search was performed on February 18, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January, 2005 to February, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Systematic reviews, randomized controlled trials, observational studies
Outpatient adult population with chronic headache and normal neurological exam
Studies reporting likelihood ratio of clinical variables for a significant intracranial abnormality
English language studies
2005-present
Exclusion Criteria
Studies which report outcomes for persons with seizures, focal symptoms, recent/new onset headache, change in presentation, thunderclap headache, and headache due to trauma
Persons with abnormal neurological examination
Case reports
Outcomes of Interest
Primary Outcome
Probability for intracranial abnormality
Secondary Outcome
Patient relief from anxiety
System service use
System costs
Detection rates for significant abnormalities in MRI and CT scans
Summary of Findings
Effectiveness
One systematic review, 1 small RCT, and 1 observational study met the inclusion and exclusion criteria. The systematic review completed by Detsky, et al. reported the likelihood ratios of specific clinical variables to predict significant intracranial abnormalities. The RCT completed by Howard et al., evaluated whether neuroimaging persons with chronic headache increased or reduced patient anxiety. The prospective observational study by Sempere et al., provided evidence for the pre-test probability of intracranial abnormalities in persons with chronic headache as well as minimal data on the comparative effectiveness of CT and MRI to detect intracranial abnormalities.
Outcome 1: Pre-test Probability.
The pre-test probability is usually related to the prevalence of the disease and can be adjusted depending on the characteristics of the population. The study by Sempere et al. determined the pre-test probability (prevalence) of significant intracranial abnormalities in persons with chronic headaches defined as headache experienced for at least a 4 week duration with a normal neurological exam. There is a pre-test probability of 0.9% (95% CI 0.5, 1.4) in persons with chronic headache and normal neurological exam. The highest pre-test probability of 5 found in persons with cluster headaches. The second highest, that of 3.7, was reported in persons with indeterminate type headache. There was a 0.75% rate of incidental findings.
Likelihood ratios for detecting a significant abnormality
Clinical findings from the history and physical may be used as screening test to predict abnormalities on neuroimaging. The extent to which the clinical variable may be a good predictive variable can be captured by reporting its likelihood ratio. The likelihood ratio provides an estimate of how much a test result will change the odds of having a disease or condition. The positive likelihood ratio (LR+) tells you how much the odds of having the disease increases when a test is positive. The negative likelihood ratio (LR-) tells you how much the odds of having the disease decreases when the test is negative.
Detsky et al., determined the likelihood ratio for specific clinical variable from 11 studies. There were 4 clinical variables with both statistically significant positive and negative likelihood ratios. These included: abnormal neurological exam (LR+ 5.3, LR- 0.72), undefined headache (LR+ 3.8, LR- 0.66), headache aggravated by exertion or valsalva (LR+ 2.3, LR- 0.70), and headache with vomiting (LR+ 1.8, and LR- 0.47). There were two clinical variables with a statistically significant positive likelihood ratio and non significant negative likelihood ratio. These included: cluster-type headache (LR+ 11, LR- 0.95), and headache with aura (LR+ 12.9, LR- 0.52). Finally, there were 8 clinical variables with both statistically non significant positive and negative likelihood ratios. These included: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, and migraine type headache.
Outcome 2: Relief from Anxiety
Howard et al. completed an RCT of 150 persons to determine if neuroimaging for headaches was anxiolytic or anxiogenic. Persons were randomized to receiving either an MRI scan or no scan for investigation of their headache. The study population was stratified into those persons with a Hospital Anxiety and Depression scale (HADS) > 11 (the high anxiety and depression group) and those < 11 (the low anxiety and depression) so that there were 4 groups:
Group 1: High anxiety and depression, no scan group
Group 2: High anxiety and depression, scan group
Group 3: Low anxiety and depression, no scan group
Group 4: Low anxiety and depression, scan group
Anxiety
There was no evidence for any overall reduction in anxiety at 1 year as measured by a visual analogue scale of ‘level of worry’ when analysed by whether the person received a scan or not. Similarly, there was no interaction between anxiety and depression status and whether a scan was offered or not on patient anxiety. Anxiety did not decrease at 1 year to any statistically significant degree in the high anxiety and depression group (HADS positive) compared with the low anxiety and depression group (HADS negative).
There are serious methodological limitations in this study design which may have contributed to these negative results. First, when considering the comparison of ‘scan’ vs. ‘no scan’ groups, 12 people (16%) in the ‘no scan group’ actually received a scan within the follow up year. If indeed scanning does reduce anxiety then this contamination of the ‘no scan’ group may have reduced the effect between the groups results resulting in a non significant difference in anxiety scores between the ‘scanned’ and the ‘no scan’ group. Second, there was an inadequate sample size at 1 year follow up in each of the 4 groups which may have contributed to a Type II statistical error (missing a difference when one may exist) when comparing scan vs. no scan by anxiety and depression status. Therefore, based on the results and study limitations it is inconclusive as to whether scanning reduces anxiety.
Outcome 3: System Services
Howard et al., considered services used and system costs a secondary outcome. These were determined by examining primary care case notes at 1 year for consultation rates, symptoms, further investigations, and contact with secondary and tertiary care.
System Services
The authors report that the use of neurologist and psychiatrist services was significantly higher for those persons not offered as scan, regardless of their anxiety and depression status (P<0.001 for neurologist, and P=0.033 for psychiatrist)
Outcome 4: System Costs
System Costs
There was evidence of statistically significantly lower system costs if persons with high levels of anxiety and depression (Hospital Anxiety and Depression Scale score >11) were provided with a scan (P=0.03 including inpatient costs, and 0.047 excluding inpatient costs).
Comparative Effectiveness of CT and MRI Scans
One study reported the detection rate for significant intracranial abnormalities using CT and MRI. In a cohort of 1876 persons with a non acute headache defined as any type of headache that had begun at least 4 weeks before enrolment Sempere et al. reported that the detection rate was 19/1432 (1.3%) using CT and 4/444 (0.9%) using MRI. Of 119 normal CT scans 2 (1.7%) had significant intracranial abnormality on MRI. The 2 cases were a small meningioma, and an acoustic neurinoma.
Summary
The evidence presented can be summarized as follows:
Pre-test Probability
Based on the results by Sempere et al., there is a low pre-test probability for intracranial abnormalities in persons with chronic headaches and a normal neurological exam (defined as headaches experiences for a minimum of 4 weeks). The Grade quality of evidence supporting this outcome is very low.
Likelihood Ratios
Based on the systematic review by Detsky et al., there is a statistically significant positive and negative likelihood ratio for the following clinical variables: abnormal neurological exam, undefined headache, headache aggravated by exertion or valsalva, headache with vomiting. Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al. there is a statistically significant positive likelihood ratio but non statistically significant negative likelihood ratio for the following clinical variables: cluster headache and headache with aura. The Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al., there is a non significant positive and negative likelihood ratio for the following clinical variables: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, migraine type headache. The Grade quality of evidence supporting this outcome is very low.
Relief from Anxiety
Based on the RCT by Howard et al., it is inconclusive whether neuroimaging scans in persons with a chronic headache are anxiolytic. The Grade quality of evidence supporting this outcome is low.
System Services
Based on the RCT by Howard et al. scanning persons with chronic headache regardless of their anxiety and/or depression level reduces service use. The Grade quality of evidence is low.
System Costs
Based on the RCT by Howard et al., scanning persons with a score greater than 11 on the High Anxiety and Depression Scale reduces system costs. The Grade quality of evidence is moderate.
Comparative Effectiveness of CT and MRI Scans
There is sparse evidence to determine the relative effectiveness of CT compared with MRI scanning for the detection of intracranial abnormalities. The Grade quality of evidence supporting this is very low.
Economic Analysis
Ontario Perspective
Volumes for neuroimaging of the head i.e. CT and MRI scans, from the Ontario Health Insurance Plan (OHIP) data set were used to investigate trends in the province for Fiscal Years (FY) 2004-2009.
Assumptions were made in order to investigate neuroimaging of the head for the indication of headache. From the literature, 27% of all CT and 13% of all MRI scans for the head were assumed to include an indication of headache. From that same retrospective chart review and personal communication with the author 16% of CT scans and 4% of MRI scans for the head were for the sole indication of headache. From the Ministry of Health and Long-Term Care (MOHLTC) wait times data, 73% of all CT and 93% of all MRI scans in the province, irrespective of indication were outpatient procedures.
The expenditure for each FY reflects the volume for that year and since volumes have increased in the past 6 FYs, the expenditure has also increased with a pay-out reaching 3.0M and 2.8M for CT and MRI services of the head respectively for the indication of headache and a pay-out reaching 1.8M and 0.9M for CT and MRI services of the head respectively for the indication of headache only in FY 08/09.
Cost per Abnormal Finding
The yield of abnormal finding for a CT and MRI scan of the head for the indication of headache only is 2% and 5% respectively. Based on these yield a high-level estimate of the cost per abnormal finding with neuroimaging of the head for headache only can be calculated for each FY. In FY 08/09 there were 37,434 CT and 16,197 MRI scans of the head for headache only. These volumes would generate a yield of abnormal finding of 749 and 910 with a CT scan and MRI scan respectively. The expenditure for FY 08/09 was 1.8M and 0.9M for CT and MRI services respectively. Therefore the cost per abnormal finding would be $2,409 for CT and $957 for MRI. These cost per abnormal finding estimates were limited because they did not factor in comparators or the consequences associated with an abnormal reading or FNs. The estimates only consider the cost of the neuroimaging procedure and the yield of abnormal finding with the respective procedure.
PMCID: PMC3377587  PMID: 23074404
2.  Understanding social anxiety as a risk for alcohol use disorders: Fear of scrutiny, not social interaction fears, prospectively predicts alcohol use disorders 
Journal of psychiatric research  2008;43(4):477-483.
Increasing evidence indicates that social anxiety may be a premorbid risk factor for alcohol use disorders (AUD). The aim of this study was to replicate and extend previous work examining whether social anxiety is a risk factor for AUD by evaluating both the temporal antecedence and non-spuriousness of this relationship. We also examined whether social anxiety first-order factors (social interaction anxiety, observation anxieties) served as specific predictors of AUD. A non-referred sample of 404 psychologically healthy young adults (i.e. free from current or past Axis I psychopathology) was prospectively followed over approximately two years. Social anxiety (but not depression or trait anxiety) at baseline significantly predicted subsequent AUD onset. The relationship between social anxiety and AUD remained even after controlling for relevant variables (gender, depression, trait anxiety). Further, social anxiety first-order factors differentially predicted AUD onset, such that observation anxieties (but not social interaction anxiety) were prospectively linked to AUD onset. This study provides further support that social anxiety (and fear of scrutiny specifically) appears to serve as an important and potentially specific AUD-related variable that deserves serious attention as a potential vulnerability factor.
doi:10.1016/j.jpsychires.2008.04.012
PMCID: PMC2778223  PMID: 18547587
Alcohol use disorders; Social anxiety; Social phobia; Prospective studies; Comorbidity; Risk factors
3.  Cross-National Analysis of the Associations among Mental Disorders and Suicidal Behavior: Findings from the WHO World Mental Health Surveys 
PLoS Medicine  2009;6(8):e1000123.
Using data from over 100,000 individuals in 21 countries participating in the WHO World Mental Health Surveys, Matthew Nock and colleagues investigate which mental health disorders increase the odds of experiencing suicidal thoughts and actual suicide attempts, and how these relationships differ across developed and developing countries.
Background
Suicide is a leading cause of death worldwide. Mental disorders are among the strongest predictors of suicide; however, little is known about which disorders are uniquely predictive of suicidal behavior, the extent to which disorders predict suicide attempts beyond their association with suicidal thoughts, and whether these associations are similar across developed and developing countries. This study was designed to test each of these questions with a focus on nonfatal suicide attempts.
Methods and Findings
Data on the lifetime presence and age-of-onset of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) mental disorders and nonfatal suicidal behaviors were collected via structured face-to-face interviews with 108,664 respondents from 21 countries participating in the WHO World Mental Health Surveys. The results show that each lifetime disorder examined significantly predicts the subsequent first onset of suicide attempt (odds ratios [ORs] = 2.9–8.9). After controlling for comorbidity, these associations decreased substantially (ORs = 1.5–5.6) but remained significant in most cases. Overall, mental disorders were equally predictive in developed and developing countries, with a key difference being that the strongest predictors of suicide attempts in developed countries were mood disorders, whereas in developing countries impulse-control, substance use, and post-traumatic stress disorders were most predictive. Disaggregation of the associations between mental disorders and nonfatal suicide attempts showed that these associations are largely due to disorders predicting the onset of suicidal thoughts rather than predicting progression from thoughts to attempts. In the few instances where mental disorders predicted the transition from suicidal thoughts to attempts, the significant disorders are characterized by anxiety and poor impulse-control. The limitations of this study include the use of retrospective self-reports of lifetime occurrence and age-of-onset of mental disorders and suicidal behaviors, as well as the narrow focus on mental disorders as predictors of nonfatal suicidal behaviors, each of which must be addressed in future studies.
Conclusions
This study found that a wide range of mental disorders increased the odds of experiencing suicide ideation. However, after controlling for psychiatric comorbidity, only disorders characterized by anxiety and poor impulse-control predict which people with suicide ideation act on such thoughts. These findings provide a more fine-grained understanding of the associations between mental disorders and subsequent suicidal behavior than previously available and indicate that mental disorders predict suicidal behaviors similarly in both developed and developing countries. Future research is needed to delineate the mechanisms through which people come to think about suicide and subsequently progress from ideation to attempts.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Suicide is a leading cause of death worldwide. Every 40 seconds, someone somewhere commits suicide. Over a year, this adds up to about 1 million self-inflicted deaths. In the USA, for example, where suicide is the 11th leading cause of death, more than 30,000 people commit suicide every year. The figures for nonfatal suicidal behavior (suicidal thoughts or ideation, suicide planning, and suicide attempts) are even more shocking. Globally, suicide attempts, for example, are estimated to be 20 times as frequent as completed suicides. Risk factors for nonfatal suicidal behaviors and for suicide include depression and other mental disorders, alcohol or drug abuse, stressful life events, a family history of suicide, and having a friend or relative commit suicide. Importantly, nonfatal suicidal behaviors are powerful predictors of subsequent suicide deaths so individuals who talk about killing themselves must always be taken seriously and given as much help as possible by friends, relatives, and mental-health professionals.
Why Was This Study Done?
Experts believe that it might be possible to find ways to decrease suicide rates by answering three questions. First, which individual mental disorders are predictive of nonfatal suicidal behaviors? Although previous studies have reported that virtually all mental disorders are associated with an increased risk of suicidal behaviors, people often have two or more mental disorders (“comorbidity”), so many of these associations may reflect the effects of only a few disorders. Second, do some mental disorders predict suicidal ideation whereas others predict who will act on these thoughts? Finally, are the associations between mental disorders and suicidal behavior similar in developed countries (where most studies have been done) and in developing countries? By answering these questions, it should be possible to improve the screening, clinical risk assessment, and treatment of suicide around the world. Thus, in this study, the researchers undertake a cross-national analysis of the associations among mental disorders (as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV]) and nonfatal suicidal behaviors.
What Did the Researchers Do and Find?
The researchers collected and analyzed data on the lifetime presence and age-of-onset of mental disorders and of nonfatal suicidal behaviors in structured interviews with nearly 110,000 participants from 21 countries (part of the World Health Organization's World Mental Health Survey Initiative). The lifetime presence of each of the 16 disorders considered (mood disorders such as depression; anxiety disorders such as post-traumatic stress disorder [PTSD]; impulse-control disorders such as attention deficit/hyperactivity disorder; and substance misuse) predicted first suicide attempts in both developed and developing countries. However, the increased risk of a suicide attempt associated with each disorder varied. So, for example, in developed countries, after controlling for comorbid mental disorders, major depression increased the risk of a suicide attempt 3-fold but drug abuse/dependency increased the risk only 2-fold. Similarly, although the strongest predictors of suicide attempts in developed countries were mood disorders, in developing countries the strongest predictors were impulse-control disorders, substance misuse disorders, and PTSD. Other analyses indicate that mental disorders were generally more predictive of the onset of suicidal thoughts than of suicide plans and attempts, but that anxiety and poor impulse-control disorders were the strongest predictors of suicide attempts in both developed and developing countries.
What Do These Findings Mean?
Although this study has several limitations—for example, it relies on retrospective self-reports by study participants—its findings nevertheless provide a more detailed understanding of the associations between mental disorders and subsequent suicidal behaviors than previously available. In particular, its findings reveal that a wide range of individual mental disorders increase the chances of an individual thinking about suicide in both developed and developing countries and provide new information about the mental disorders that predict which people with suicidal ideas will act on such thoughts. However, the findings also show that only half of people who have seriously considered killing themselves have a mental disorder. Thus although future suicide prevention efforts should include a focus on screening and treating mental disorders, ways must also be found to identify the many people without mental disorders who are at risk of suicidal behaviors.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000123.
The US National Institute of Mental Health provides information about suicide in the US: statistics and prevention
The UK National Health Service provides information about suicide, including statistics about suicide in the UK and links to other resources
The World Health Organization provides global statistics about suicide and information on suicide prevention
MedlinePlus provides links to further information and advice about suicide and about mental health (in English and Spanish)
Further details about the World Mental Health Survey Initiative and about DSM-IV are available
doi:10.1371/journal.pmed.1000123
PMCID: PMC2717212  PMID: 19668361
4.  Impact of parental history of substance use disorders on the clinical course of anxiety disorders 
Background
Among the psychological difficulties seen in children of parents with substance use problems, the anxiety disorders are among the most chronic conditions. Although children of alcoholic parents often struggle with the effects of parental substance use problems long into adulthood, empirical investigations of the influence of parental substance use disorders on the course of anxiety disorders in adult offspring are rare. The purpose of this study was to examine prospectively the relationship between parental substance use disorders and the course of anxiety disorders in adulthood over the course of 12 years.
Methods
Data on 618 subjects were derived from the Harvard/Brown Anxiety Research Project (HARP), a longitudinal naturalistic investigation of the clinical course of multiple anxiety disorders. Kaplan-Meier survival estimates were used to calculate probabilities of time to anxiety disorder remission and relapse. Proportional hazards regressions were conducted to determine whether the likelihood of remission and relapse for specific anxiety disorders was lower for those who had a history of parental substance use disorders than for individuals without this parental history.
Results
Adults with a history of parental substance use disorders were significantly more likely to be divorced and to have a high school level of education. History of parental substance use disorder was a significant predictor of relapse of social phobia and panic disorders.
Conclusion
These findings provide compelling evidence that adult children of parents with substance use disorders are more likely to have relapses of social phobia and panic disorders. Clinicians who treat adults with anxiety disorders should assess parental substance use disorders and dependence histories. Such information may facilitate treatment planning with regards to their patients' level of vulnerability to perceive scrutiny by others in social situations, and ability to maintain a long-term panic-free state.
doi:10.1186/1747-597X-2-13
PMCID: PMC1866228  PMID: 17466067
5.  A longitudinal investigation of psychological morbidity in patients with ovarian cancer 
British Journal of Cancer  2008;99(11):1794-1801.
Ovarian cancer patients may experience psychological disorders due to the aggressive nature of the illness and treatment. We investigated the presence of psychological disorders longitudinally in women with a new diagnosis of ovarian cancer and the factors that predicted development and maintenance of these disorders. Patients were assessed in a prospective longitudinal study at the beginning of chemotherapy treatment, mid-treatment, end of treatment and 3 months follow-up for depression, anxiety, perceived social support, neuroticism and cognitive strategies to control unwanted thoughts. A total of 121 patients were recruited and 85 patients were assessed at all four time points. Three different longitudinal profiles of anxiety and depression caseness were found: non-cases (never cases), occasional cases (cases on at least one but not all four occasions) and stable cases (cases on all four occasions). Most of the women were occasional cases of anxiety (52%, 44), whereas for depression, the majority of women were non-cases (55%, 47). A subset of patients were stable cases of anxiety (22%, 19). Neuroticism and marital status were significant independent predictors of anxiety caseness profile. Neuroticism and use of anti-depressants were independent predictors of depression caseness profile. Social support was not related to psychological morbidity.
doi:10.1038/sj.bjc.6604770
PMCID: PMC2600707  PMID: 19002175
ovarian cancer; anxiety; depression; longitudinal study
6.  The role of fear and anxiety in the familial risk for major depression: a three-generation study 
Psychological medicine  2008;38(11):1543-1556.
Background
The overlap between anxiety and major depressive disorder (MDD), the increased risk for depression and anxiety in offspring of depressed parents, the sequence of onset with anxiety preceding MDD, and anxiety as a predictor of depression are well established. The specificity of anxiety disorders in these relationships is unclear. This study, using a longitudinal high-risk design, examined whether anxiety disorders associated with the emotions fear and anxiety mediate the association between parental and offspring depression.
Method
Two hundred and twenty-four second-generation and 155 third-generation descendants at high and low risk for depression because of MDD in the first generation were interviewed over 20 years. Probit and Cox proportional hazard models were fitted with generation 2 (G2) or G3 depression as the outcome and parental MDD as the predictor. In G2 and G3, fear- (phobia or panic) and anxiety-related [overanxious or generalized anxiety disorder (GAD)] disorders were examined as potential mediators of increased risk for offspring depression, due to parental MDD.
Results
In G2, fear-related disorders met criteria for mediating the association between parental MDD and offspring MDD whereas anxiety-related disorders did not. These results were consistent, regardless of the analytic methods used. Further investigation of the mediating effect of fear-related disorders by age of onset of offspring MDD suggests that the mediating effect occurs primarily in adolescent onset MDD. The results for G3 appear to follow similar patterns.
Conclusions
These findings support the separation of anxiety disorders into at least two distinct forms, particularly when examining their role in the etiology of depression.
doi:10.1017/S0033291708002894
PMCID: PMC2904071  PMID: 18275630
Anxiety; depression; fear; mediator; multi-generation
7.  Patterns of co-morbidity with anxiety disorders in Chinese women with recurrent major depression 
Psychological Medicine  2011;42(6):1239-1248.
Background
Studies conducted in Europe and the USA have shown that co-morbidity between major depressive disorder (MDD) and anxiety disorders is associated with various MDD-related features, including clinical symptoms, degree of familial aggregation and socio-economic status. However, few studies have investigated whether these patterns of association vary across different co-morbid anxiety disorders. Here, using a large cohort of Chinese women with recurrent MDD, we examine the prevalence and associated clinical features of co-morbid anxiety disorders.
Method
A total of 1970 female Chinese MDD patients with or without seven co-morbid anxiety disorders [including generalized anxiety disorder (GAD), panic disorder, and five phobia subtypes] were ascertained in the CONVERGE study. Generalized linear models were used to model association between co-morbid anxiety disorders and various MDD features.
Results
The lifetime prevalence rate for any type of co-morbid anxiety disorder is 60.2%. Panic and social phobia significantly predict an increased family history of MDD. GAD and animal phobia predict an earlier onset of MDD and a higher number of MDD episodes, respectively. Panic and GAD predict a higher number of DSM-IV diagnostic criteria. GAD and blood-injury phobia are both significantly associated with suicidal attempt with opposite effects. All seven co-morbid anxiety disorders predict higher neuroticism.
Conclusions
Patterns of co-morbidity between MDD and anxiety are consistent with findings from the US and European studies; the seven co-morbid anxiety disorders are heterogeneous when tested for association with various MDD features.
doi:10.1017/S003329171100273X
PMCID: PMC3339636  PMID: 22126712
Co-morbid anxiety disorders; major depression
8.  Pregnant Mothers with Resolved Anxiety Disorders and Their Offspring Have Reduced Heart Rate Variability: Implications for the Health of Children 
PLoS ONE  2013;8(12):e83186.
Objective
Active anxiety disorders have lasting detrimental effects on pregnant mothers and their offspring but it is unknown if historical, non-active, maternal anxiety disorders have similar effects. Anxiety-related conditions, such as reduced autonomic cardiac control, indicated by reduced heart rate variability (HRV) could persist despite disorder resolution, with long-term health implications for mothers and children. The objective in this study is to test the hypotheses that pregnant mothers with a history of, but not current anxiety and their children have low HRV, predicting anxiety-like offspring temperaments.
Methods
The participants in this case-control study consist of 56 women during their first trimester and their offspring (15 male, 29 female). Women had a history of an anxiety disorder (n=22) or no psychopathology (n=34) determined using the Mini-International Neuropsychiatric Interview. The main outcome measures were indices of autonomic cardiac control including root mean square of successive differences (RMSSD) and high frequency (HF) variability. Children’s fearfulness was also assessed using the Laboratory Temperament Assessment Battery (Lab-TAB)-Locomotor Version.
Results
HRV was lower in women and children in the past anxiety group compared to controls. HRV measures for mothers and children were positively correlated in the anxiety group only. In all children, low HRV measures at 2-4 months were associated with a higher chance of fearful behavior at 9-10 months.
Conclusions
Pregnant women with previous but not current anxiety and their children have low HRV. Children with low HRV tend to show more fearfulness. These findings have implications for identifying children at risk of anxiety disorders and point to possible underlying mechanisms of child psychopathology.
doi:10.1371/journal.pone.0083186
PMCID: PMC3858358  PMID: 24340091
9.  The association of personality disorders with the prospective 7-year course of anxiety disorders 
Psychological medicine  2010;41(5):1019-1028.
Background
This study prospectively examined the natural clinical course of six anxiety disorders over 7 years of follow-up in individuals with personality disorders (PDs) and/or major depressive disorder. Rates of remission, relapse, new episode onset and chronicity of anxiety disorders were examined for specific associations with PDs.
Method
Participants were 499 patients with anxiety disorders in the Collaborative Longitudinal Personality Disorders Study, who were assessed with structured interviews for psychiatric disorders at yearly intervals throughout 7 years of follow-up. These data were used to determine probabilities of changes in disorder status for social phobia (SP), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder and panic disorder with agoraphobia.
Results
Estimated remission rates for anxiety disorders in this study group ranged from 73% to 94%. For those patients who remitted from an anxiety disorder, relapse rates ranged from 34% to 67%. Rates for new episode onsets of anxiety disorders ranged from 3% to 17%. Specific PDs demonstrated associations with remission, relapse, new episode onsets and chronicity of anxiety disorders. Associations were identified between schizotypal PD with course of SP, PTSD and GAD; avoidant PD with course of SP and OCD; obsessive-compulsive PD with course of GAD, OCD, and agoraphobia; and borderline PD with course of OCD, GAD and panic with agoraphobia.
Conclusions
Findings suggest that specific PD diagnoses have negative prognostic significance for the course of anxiety disorders underscoring the importance of assessing and considering PD diagnoses in patients with anxiety disorders.
doi:10.1017/S0033291710001777
PMCID: PMC3606880  PMID: 20836909
Chronicity; anxiety disorders; personality disorders; relapse; remission
10.  Long-Term Use of Benzodiazepines in Participants with Comorbid Anxiety and Alcohol Use Disorders 
Background
Although the only widely accepted role for benzodiazepines in alcohol dependence is the treatment of withdrawal syndromes, they are frequently prescribed outside of this clinical setting. There is little empirical evidence to guide the rational use of benzodiazepines in the common clinical situation where anxiety disorders are comorbid with alcohol use disorders (AUD). Since January 1989, the Harvard Anxiety Research Program has naturalistically monitored the prospective clinical course of people with anxiety disorders, some of whom had a history of AUD. Earlier research showed that the use of benzodiazepines was not significantly associated with the presence or absence of a history of an AUD over the first year of follow-up. This report extends that investigation.
Methods
Using standard parametric analytic methods, patterns of benzodiazepine use (routinely prescribed medication and as-needed [PRN] use) among participants receiving benzodiazepine treatment was prospectively examined over the course of 12 years. Differences in benzodiazepine usage patterns were examined in each year of follow-up between participants who did (n = 120) and did not (n = 425) have a new episode of AUD. Using proportional hazards regression analysis, benzodiazepine usage levels were examined as predictors of recovery and recurrence of AUD. Additionally, random-effects regression analyses were used to examine the patterns of benzodiazepine use before and after the onset of a prospectively observed episode of AUD.
Results
Benzodiazepine usage levels remained stable for the full sample over the course of the 12 years. Benzodiazepine use did not distinguish participants who had a new AUD from those who did not. Over the 12 years of follow-up, participants who had an AUD used more PRN medication in years five to eight. This difference reached statistical significance but was not clinically significant. Benzodiazepine usage levels did not predict recovery or recurrence in AUD subjects. Neither the total dose nor the PRN usage of benzodiazepines was significantly associated with the onset of AUD, but when combined into a measure of any benzodiazepine use, a relationship between increased use and the onset of AUD emerged.
Conclusions
For participants in the Harvard Anxiety Research Program with comorbid alcohol dependence and anxiety disorders, there was little association between the use of benzodiazepines and the occurrence of a new AUD. Neither was there a temporal relationship between the use of benzodiazepines and the onset of a new AUD. Whether or not this finding extends to a broader patient population or a group of people who present to addictions treatment awaits further investigation.
doi:10.1097/01.alc.0000175016.01790.f1
PMCID: PMC2548411  PMID: 16131848
Benzodiazepines; Alcohol Use Disorders; Harvard Anxiety Research Program; Anxiety; Comorbid Alcohol Dependence; Anxiety Disorders
11.  Influence of Psychiatric Comorbidity on Recovery and Recurrence in Generalized Anxiety Disorder, Social Phobia, and Panic Disorder: A 12-Year Prospective Study 
The American Journal of Psychiatry  2005;162(6):1179-1187.
Objective
The authors sought to observe the long-term clinical course of anxiety disorders over 12 years and to examine the influence of comorbid psychiatric disorders on recovery from or recurrence of panic disorder, generalized anxiety disorder, and social phobia.
Method
Data were drawn from the Harvard/Brown Anxiety Disorders Research Program, a prospective, naturalistic, longitudinal, multicenter study of adults with a current or past history of anxiety disorders. Probabilities of recovery and recurrence were calculated by using standard survival analysis methods. Proportional hazards regression analyses with time-varying covariates were conducted to determine risk ratios for possible comorbid psychiatric predictors of recovery and recurrence.
Results
Survival analyses revealed an overall chronic course for the majority of the anxiety disorders. Social phobia had the smallest probability of recovery after 12 years of follow-up. Moreover, patients who had prospectively observed recovery from their intake anxiety disorder had a high probability of recurrence over the follow-up period. The overall clinical course was worsened by several comorbid psychiatric conditions, including major depression and alcohol and other substance use disorders, and by comorbidity of generalized anxiety disorder and panic disorder with agoraphobia.
Conclusions
These data depict the anxiety disorders as insidious, with a chronic clinical course, low rates of recovery, and relatively high probabilities of recurrence. The presence of particular comorbid psychiatric disorders significantly lowered the likelihood of recovery from anxiety disorders and increased the likelihood of their recurrence. The findings add to the understanding of the nosology and treatment of these disorders.
doi:10.1176/appi.ajp.162.6.1179
PMCID: PMC3272761  PMID: 15930067
12.  Prevalence and Correlates of Bipolar I Disorder among Adults with Primary Youth-onset Anxiety Disorders 
Journal of affective disorders  2007;103(1-3):187-195.
Objectives
It is of potentially great public health importance to determine whether youth-onset anxiety disorders are associated with increased prevalence of subsequent bipolar I disorder (BD) among adults, and to identify risk factors for BD in this population.
Methods
The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions was used to identify respondents with social phobia, panic disorder, or generalized anxiety disorder that onset in youth (<19 years) and was not preceded by a major depressive, manic, or mixed episode (N=1,571; 572 males, 999 females). The prevalence of BD among subjects with, versus without, these youth-onset anxiety disorders was examined. Variables that could be associated with increased risk of BD among subjects with youth-onset anxiety disorders were examined, including conduct disorder, youth-onset substance use disorders (SUD), and family history of depression and/or alcoholism. Analyses were computed separately for males and females.
Results
The prevalence of BD was significantly greater among adults with, versus without, primary youth-onset anxiety disorders for both males (15.9% vs 2.7%; χ2=318.4, df=1, p<0.001) and females (13.8% vs 2.9%; χ2=346.2, df=1, p<0.001). Youth-onset anxiety disorders remained significantly associated with BD after controlling for interceding major depression, and this was true for each of the specific anxiety disorders examined. Among males with youth-onset primary anxiety disorders, conduct disorder and loaded family history of depression were associated with significantly increased risk of BD. Among females, conduct disorder and loaded family history of alcoholism were associated with significantly increased risk of BD.
Conclusions
The prevalence of BD was elevated among subjects with youth-onset primary anxiety disorders, particularly if comorbid conduct disorder was present. Future studies are needed to confirm these findings prospectively, and to develop preventive strategies for populations at risk.
doi:10.1016/j.jad.2007.01.029
PMCID: PMC2206538  PMID: 17328960
bipolar I disorder; anxiety; panic; alcohol; drug; substance
13.  Cognitive Reactivity, Implicit Associations, and the Incidence of Depression: A Two-Year Prospective Study 
PLoS ONE  2013;8(7):e70245.
Background
Cognitive reactivity to sad mood is a vulnerability marker of depression. Implicit self-depressed associations are related to depression status and reduced remission probability. It is unknown whether these cognitive vulnerabilities precede the first onset of depression.
Aim
To test the predictive value of cognitive reactivity and implicit self-depressed associations for the incidence of depressive disorders.
Methods
Prospective cohort study of 834 never-depressed individuals, followed over a two-year period. The predictive value of cognitive reactivity and implicit self-depressed associations for the onset of depressive disorders was assessed using binomial logistic regression. The multivariate model corrected for baseline levels of subclinical depressive symptoms, neuroticism, for the presence of a history of anxiety disorders, for family history of depressive or anxiety disorders, and for the incidence of negative life events.
Results
As single predictors, both cognitive reactivity and implicit self-depressed associations were significantly associated with depression incidence. In the multivariate model, cognitive reactivity was significantly associated with depression incidence, together with baseline depressive symptoms and the number of negative life events, whereas implicit self-depressed associations were not.
Conclusion
Cognitive reactivity to sad mood is associated with the incidence of depressive disorders, also when various other depression-related variables are controlled for. Implicit self-depressed associations predicted depression incidence in a bivariate test, but not when controlling for other predictors.
doi:10.1371/journal.pone.0070245
PMCID: PMC3724814  PMID: 23922962
14.  Prospective study of risk factors for suicidal behavior in individuals with anxiety disorders 
Psychological medicine  2012;43(7):1465-1474.
Background
Anxiety disorders are very common and increase risk for suicide attempts. Little is known about predictors of increased risk specifically among individuals with anxiety disorders. The purpose of this study was to investigate whether specific anxiety disorders and other co-morbid psychiatric disorders, physical health, or work or social functioning increased the future likelihood of a suicide attempts among individuals with anxiety disorders.
Method
In this prospective study, 676 individuals with an anxiety disorder were followed for an average of 12 years.
Results
As hypothesized, we found that post-traumatic stress disorder, major depressive disorder (MDD), intermittent depressive disorder (IDD), epilepsy, pain, and poor work and social functioning all predicted a shorter time to a suicide attempt in univariate analyses. In multivariate analyses, baseline MDD and IDD were independent predictors of time to suicide attempt, even when controlling for a past history of suicide attempt. No specific anxiety disorder was an independent predictor of time to attempt in this anxiety-disordered sample. Adding baseline physical health variables and social functioning did not improve the ability of the model to predict time to suicide attempt.
Conclusions
Mood disorders and past history of suicide attempts are the most powerful predictors of a future suicide attempt in this sample of individuals, all of whom have an anxiety disorder.
doi:10.1017/S0033291712002504
PMCID: PMC3686832  PMID: 23137440
Anxiety disorders; suicide; suicide attempts
15.  Depression and Anxiety Trajectories among Women Who Undergo an Elective Cesarean Section 
PLoS ONE  2014;9(1):e86653.
Background
Depression and anxiety are important mood changes in childbearing women. However, changes in depression and anxiety over time in women who undergo an elective cesarean section (CS) have not yet been elucidated. We aimed to characterize the trajectories of depressive and anxiety symptoms, and patterns of co-occurrence, and examined the associated predictors of depression and anxiety courses.
Methods
A prospective longitudinal study of childbearing women (N = 139) who underwent a CS was conducted. Depressive and anxiety symptoms were respectively assessed using the Edinburgh Postnatal Depression Scale and State Anxiety Inventory, in the third trimester and at 1 day, 1 week, and 1 and 6 months postpartum.
Results
Group-based modeling identified three distinct trajectories of depressive symptoms: group 1 (low, 30.9%), group 2 (mild, 41.7%), and group 3 (high, 27.3%). Four group trajectories of anxiety symptoms were identified: group 1 (low, 19.4%), group 2 (mild, 44.6%), group 3 (high, 28.8%), and group 4 (very high, 7.2%). Mild symptoms of both depression and anxiety were the most common joint trajectory. Depression trajectories were significantly related to anxiety trajectories (p<0.001). Predictors of the joint trajectory included the pre-pregnant body mass index (odds ratio (OR): 2.42, 95% confidence interval (CI): 1.1∼6.3) and a poor sleep score (OR: 3.2, 95% CI: 1.4∼7.3) in the third trimester.
Conclusions
Distinctive trajectories and co-occurrence patterns of depressive and anxiety symptoms were identified. Our findings suggest a need for greater attention to continuous assessment of psychological well-being among women who undergo an elective CS.
doi:10.1371/journal.pone.0086653
PMCID: PMC3899292  PMID: 24466190
16.  Anxiety Associations with Cardiac Symptoms, Angiographic Disease Severity, & Healthcare Utilization: The NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation 
International journal of cardiology  2013;168(3):2335-2340.
Background
Anxiety is common among patients presenting with suspected coronary artery disease (CAD). In a sample of women with signs and symptoms of ischemia, we examined three anxiety markers as predictors of CAD endpoints including: 1) cardiac symptom indicators; 2) angiographic CAD severity; and 3) healthcare utilization (cardiac hospitalizations & 5-year cardiovascular [CVD] healthcare costs).
Methods
Participants completed a baseline protocol including coronary angiogram, cardiac symptoms, psychosocial measures and a median 5.9-year follow-up to track hospitalizations. We calculated CVD costs based on cardiac hospitalizations, treatment visits, and CVD medications. Anxiety measures included anxiolytic medication use, Spielberger Trait Anxiety Inventory (STAI) scores, and anxiety disorder treatment history.
Results
The sample numbered 514 women with anxiety measure data and covariates (mean age=57.5[11.1]). One in five (20.4%) women reported using anxiolytic agents. Anxiety correlated with cardiac symptom indicators (anxiolytic use with nighttime angina & nitroglycerine use; STAI scores & anxiety disorder treatment history with nighttime angina, shortness of breath, & angina frequency). Anxiety disorder treatment history (but not STAI scores or anxiolytics) predicted less severe CAD. Anxiolytic use (but not STAI scores or anxiety disorder treatment history) predicted hospitalizations for chest pain and coronary catheterization (HR’s=2.0, 95% CI’s=1.1–4.7). Anxiety measures predicted higher 5-year CVD costs (+9.0–42.7%) irrespective of CAD severity.
Conclusions
Among women with signs and symptoms of myocardial ischemia, anxiety measures predict cardiac endpoints ranging from cardiac symptom severity to healthcare utilization. Based on these findings, anxiety may warrant greater consideration among women with suspected CAD.
doi:10.1016/j.ijcard.2013.01.036
PMCID: PMC3683077  PMID: 23410495
cardiovascular disease; women; prospective; anxiety; depression
17.  The Influence of Anxiety on the Progression of Disability 
Objectives
To determine the influence of anxiety on the progression of disability and examine possible mediators of the relationship.
Design
Community-based observational study.
Setting
Women’s Health and Aging Study I, a prospective observational study with assessments every 6 months over 3 years.
Participants
One thousand two functionally limited women aged 65 years and older.
Measurements
Anxiety symptoms were assessed with 4 questions from the Hopkins Symptom Checklist (nervous or shaky, avoidance of certain things, tense or keyed up, fearful). Participants who reported experiencing 2 or more of these symptoms at baseline were considered anxious. Anxiety as a predictor of the onset of 4 types of disability was examined using Cox proportional hazard models. Three models were tested: an unadjusted model, a model adjusted for confounding variables (age, race, vision, number of diseases, physical performance, depressive symptoms), and a mediational model (benzodiazepine use, physical activity, emotional support).
Results
Nineteen percent of women reported 2 or more symptoms of anxiety at baseline. Unadjusted models indicate that anxiety was associated with a greater risk of worsening disability: ADL disability (Hazard Risk = 1.40, 95% CI 1.10–1.79), mobility disability (HR = 1.41, 95% CI 1.06–1.86), lifting disability (HR = 1.54, 95% CI 1.20–1.97), and light housework disability (HR = 1.77, 95% CI 1.32–2.37). After adjusting for confounding variables, anxiety continued to predict the development of 2 types of disability: ADL disability (HR = 1.41, 95% CI 1.08–1.84) and light housework disability (HR = 1.56, 95% CI 1.14–2.14). Finally, benzodiazepine and psychotropic medication use, physical activity, and emotional support were not significant mediators of the effect of anxiety on the development of a disability.
Conclusion
Anxiety is a significant risk factor for the progression of disability among older women. Studies are needed to determine if treatment of anxiety delays or prevents disability.
doi:10.1111/j.1532-5415.2005.53007.x
PMCID: PMC1343490  PMID: 15667373
anxiety symptoms; disability; aged (65+)
18.  Prospective prediction of major depressive disorder from cortisol awakening responses in adolescence 
Psychoneuroendocrinology  2010;35(6):921-931.
Levels of the stress-sensitive hormone cortisol increase dramatically in the first 30-40 minutes after waking, an effect known as the cortisol awakening response (CAR). There is considerable cross-sectional evidence that psychosocial stress is associated with an increased CAR, and the CAR has been found to be altered in the presence of stress-related diseases, including Major Depressive Disorder (MDD). To date, no prospective longitudinal studies have examined whether individual differences in the CAR serve as a premorbid risk factor for MDD. In a sample of 230 late adolescents, clinical diagnoses of MDD were predicted from the CAR as well as other indicators of basal cortisol functioning gathered one year earlier, including: waking cortisol levels, bedtime cortisol levels, the size of the CAR, average cortisol, and the slope of the diurnal cortisol rhythm across the waking day. Age and gender, health and health behaviors, baseline neuroticism, exposure to stressful life events and past episodes of mood and anxiety disorders were included as covariates, to help ensure effects are attributable to the CAR rather than related variables. A higher baseline CAR was associated with a significantly increased risk of developing MDD by follow-up, even when excluding individuals with baseline MDD. No other baseline cortisol measures were significant prospective predictors of MDD. In summary, the CAR is a significant prospective risk factor for the development of MDD in young adults, providing some support for the possibility that a heightened CAR may play a role in the etiology of Major Depressive Disorder.
doi:10.1016/j.psyneuen.2009.12.007
PMCID: PMC2875344  PMID: 20079576
Hypothalamic pituitary adrenal axis; cortisol awakening response; major depressive disorder; life events; prospective; diurnal cortisol rhythms
19.  Performance of Polygenic Scores for Predicting Phobic Anxiety 
PLoS ONE  2013;8(11):e80326.
Context
Anxiety disorders are common, with a lifetime prevalence of 20% in the U.S., and are responsible for substantial burdens of disability, missed work days and health care utilization. To date, no causal genetic variants have been identified for anxiety, anxiety disorders, or related traits.
Objective
To investigate whether a phobic anxiety symptom score was associated with 3 alternative polygenic risk scores, derived from external genome-wide association studies of anxiety, an internally estimated agnostic polygenic score, or previously identified candidate genes.
Design
Longitudinal follow-up study. Using linear and logistic regression we investigated whether phobic anxiety was associated with polygenic risk scores derived from internal, leave-one out genome-wide association studies, from 31 candidate genes, and from out-of-sample genome-wide association weights previously shown to predict depression and anxiety in another cohort.
Setting and Participants
Study participants (n = 11,127) were individuals from the Nurses' Health Study and Health Professionals Follow-up Study.
Main Outcome Measure
Anxiety symptoms were assessed via the 8-item phobic anxiety scale of the Crown Crisp Index at two time points, from which a continuous phenotype score was derived.
Results
We found no genome-wide significant associations with phobic anxiety. Phobic anxiety was also not associated with a polygenic risk score derived from the genome-wide association study beta weights using liberal p-value thresholds; with a previously published genome-wide polygenic score; or with a candidate gene risk score based on 31 genes previously hypothesized to predict anxiety.
Conclusion
There is a substantial gap between twin-study heritability estimates of anxiety disorders ranging between 20–40% and heritability explained by genome-wide association results. New approaches such as improved genome imputations, application of gene expression and biological pathways information, and incorporating social or environmental modifiers of genetic risks may be necessary to identify significant genetic predictors of anxiety.
doi:10.1371/journal.pone.0080326
PMCID: PMC3835914  PMID: 24278274
20.  Predictors of First Lifetime Onset of Major Depressive Disorder in Young Adulthood 
The first onset of major depressive disorder (MDD) most frequently occurs in young adulthood. However, few studies have examined predictors of first lifetime MDD during this high-risk period. The present study examined a broad range of demographic, clinical, and psychosocial variables as prospective predictors of first onset of MDD in a large community sample of young adults (N = 502) from the Oregon Adolescent Depression Project. Between ages 19-31, 35.3% of the sample had a first lifetime MDD episode. Female gender, familial loading of mood disorders, history of childhood sexual abuse, prior history of anxiety disorder, poor self-reported physical health, and subthreshold depressive symptoms significantly predicted MDD onset. In a multivariate model, female gender, familial loading of mood disorders, and subthreshold depression each contributed unique variance in predicting first lifetime MDD. This model had a moderate-to-large effect in predicting MDD onset. Gender did not moderate the other predictors, and the magnitude of the effects did not diminish over the course of the follow-up. These findings indicate that a number of risk factors significantly predict first lifetime MDD in young adulthood, and that simple multivariate risk models may be useful for identifying individuals at high risk for MDD.
doi:10.1037/a0029567
PMCID: PMC3570686  PMID: 22889243
major depressive disorder; onset; risk; young adulthood
21.  Two-Year Course of Generalized Anxiety Disorder, Social Anxiety Disorder, and Panic Disorder in a Longitudinal Sample of African American Adults 
Objective
Anxiety disorders are the most common group of psychiatric disorders in adults. In addition to high prevalence, anxiety disorders are associated with significant functional impairment, and published research has consistently found them to have a chronic course. To date, very little research has explored the clinical characteristics and prospective course of anxiety disorders in racial and ethnic minority samples. The aims of this paper are to present clinical and demographic characteristics at intake and prospective two-year course findings in a sample of African American adults.
Methods
Data are presented from 152 African Americans diagnosed with generalized anxiety disorder (GAD, n = 94), social anxiety disorder (SAD, n = 85), and panic disorder with agoraphobia (PDA, n = 77) who are participating in the Harvard/Brown Anxiety Research Project-Phase II (HARP-II). HARP-II is an observational, prospective, longitudinal study of the course of anxiety disorders. Participants were interviewed at intake and annually for 2 years of follow-up. Probabilities of recovery over two years of follow-up were calculated using standard survival analysis methods.
Results and Conclusions
Survival analyses revealed a chronic course for all anxiety disorders, with rates of recovery of 0.23, 0.07, and 0.00 over two years for GAD, SAD, and PDA, respectively. These rates of recovery were lower than those reported in predominantly Non-Latino White longitudinal samples, especially for SAD and PDA, suggesting that anxiety disorders may have a more chronic course for African Americans, with increased psychosocial impairment and high rates of co-morbid Axis-I disorders. Clinical implications of these findings are discussed.
doi:10.1037/a0034382
PMCID: PMC3951438  PMID: 24041233
anxiety disorders; longitudinal course; African American; recovery; social phobia; social anxiety disorder; generalized anxiety disorder; panic disorder; agoraphobia
22.  THE IMPACT OF STRESSFUL LIFE EVENTS ON RELAPSE OF GENERALIZED ANXIETY DISORDER 
Depression and anxiety  2012;29(5):386-391.
Background
Stressful life events (SLEs) are associated with the onset of psychiatric disorders but little is known about the effects of SLEs on individuals already diagnosed with an anxiety disorder, particularly generalized anxiety disorder (GAD) in which worry about life events is a defining characteristic. This study examined the impact of SLEs on relapse in adults already diagnosed with GAD.
Methods
Data are obtained from the Harvard/Brown Anxiety Research Project (HARP), a naturalistic longitudinal study of adults with a current or past history of anxiety disorders. One hundred and twelve adults recovered from an episode of GAD and 27 subsequently relapsed during the study. Eight categories of SLEs were assessed via interview and were examined as predictors of GAD relapse.
Results
An increased total number of SLEs was associated with a higher cumulative probability of relapse into episode of GAD and there was a nonsignificant statistical trend indicating specific categories of SLEs including health, death, and family/friends/household were related to an increased probability of relapse into episodes of GAD.
Conclusions
SLEs impact the course of GAD and certain types of stressors may be more relevant to symptomatology than others. The change and uncertainty associated with SLEs may exacerbate existing worry tendencies even among those who have recovered from GAD.
doi:10.1002/da.20919
PMCID: PMC3667630  PMID: 22431499
anxiety; course; adults; longitudinal; psychiatric
23.  Prediction of “Fear” Acquisition in Healthy Control Participants in a De Novo Fear-Conditioning Paradigm 
Behavior modification  2007;31(1):32-51.
Studies using fear-conditioning paradigms have found that anxiety patients are more conditionable than individuals without these disorders, but these effects have been demonstrated inconsistently. It is unclear whether these findings have etiological significance, or whether enhanced conditionability is linked only to certain anxiety characteristics. To further examine these issues, we assessed the predictive significance of relevant subsyndromal characteristics in 72 healthy adults, including measures of worry, avoidance, anxious mood, depressed mood, and fears of anxiety symptoms (anxiety sensitivity), as well as the dimensions of neuroticism and extraversion. Of these variables, we found that the combination of higher levels of subsyndromal worry and lower levels of behavioral avoidance predicted heightened conditionability, raising questions about the etiological significance of these variables in the acquisition or maintenance of anxiety disorders. In contrast, we found that anxiety sensitivity was more linked to individual differences in orienting response than differences in conditioning per se.
doi:10.1177/0145445506295054
PMCID: PMC1764631  PMID: 17179530
Fear conditioning; etiology; worry; avoidance; anxiety sensitivity; psychophysiology
24.  Anxiety Sensitivity and Pain-related Anxiety in the Prediction of Fear Responding to Bodily Sensations: A Laboratory Test 
Journal of psychosomatic research  2010;70(3):258-266.
Objective
The present investigation sought to examine the simultaneous effects of anxiety sensitivity and pain-related anxiety on fear and anxious responding to a 10% carbon dioxide enriched air challenge.
Methods
Participants included 247 adults (53% women; age M = 21.91 years, SD = 8.41) recruited from the community. At the laboratory, participants were administered a structured clinical interview, completed a battery of self-report measures, and underwent a 10% carbon dioxide enriched air challenge.
Results
Both anxiety sensitivity and pain-related anxiety were significantly and uniquely predictive of post-challenge panic attacks, total post-challenge panic attack symptoms, and intensity of cognitive panic attack symptoms. Anxiety sensitivity, but not pain-related anxiety, also was predictive of post-challenge physical panic symptoms. The observed significant effects for both anxiety sensitivity and pain-related anxiety were evident above and beyond the variance accounted for by gender, age, current level of non-specific bodily pain, and negative affectivity. Neither anxiety sensitivity nor pain-related anxiety was significantly predictive of change in anxiety focused on bodily sensations or heart rate.
Conclusion
Results suggest that anxiety sensitivity and pain-related anxiety, although related to one another, may be independently important variables underlying fear reactivity to bodily sensations.
doi:10.1016/j.jpsychores.2010.07.011
PMCID: PMC3052923  PMID: 21334497
Panic; Anxiety; Anxiety Sensitivity; Pain-anxiety; Pain
25.  ANXIETY SENSITIVITY AS A PREDICTOR OF THE CLINICAL COURSE OF PANIC DISORDER: A 1-YEAR FOLLOW-UP STUDY 
Depression and anxiety  2009;26(4):335-342.
Background
There is evidence that negative affect (NA) and anxiety sensitivity (AS) predict the development of anxiety disorders, particularly panic disorder (PD). The main purpose of this study was to examine whether NA and AS will also predict the clinical course of PD.
Methods
Participants were 136 individuals with a DSM-III-R diagnosis of PD (with or without agoraphobia) enrolled in a naturalistic and longitudinal study of anxiety disorders, the Harvard/Brown Anxiety Research Project (HARP). Participants were administered the Anxiety Sensitivity Index and the Negative Affect Scales of the Positive and Negative Affect Schedule-Expanded Form (PANAS-X-NA) and their percentage of time in PD episode was followed for 1 year after the administration of the measures.
Results
Multiple regression analyses indicated that AS, but not NA, was a significant predictor of percentage of time in PD episode after controlling for previous time in PD episodes, comorbid depression, other anxiety disorders, and exposure to psychopharmacological and behavioral treatments. As expected, the Physical Concerns subscale of the Anxiety Sensitivity Index had a significant independent contribution in predicting the course of the disorder.
Conclusions
Overall, these findings suggest that AS, as a unique construct, may be predictive of the amount of time patients are in episode of PD.
doi:10.1002/da.20423
PMCID: PMC3675878  PMID: 19133700
panic disorder; anxiety sensitivity; negative affect; clinical course; anxiety disorders; longitudinal studies; risk factors

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