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1.  Course and Severity of Maternal Depression: Associations with Family Functioning and Child Adjustment 
Journal of youth and adolescence  2008;37(8):906-916.
Number of lifetime episodes, duration of current episode, and severity of maternal depression were investigated in relation to family functioning and child adjustment. Participants were the 151 mother–child pairs in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) child multi-site study. Mothers were diagnosed with Major Depressive Disorder; children (80 males and 71 females) ranged in age from 7 to 17 years. Measures of child adjustment included psychiatric diagnoses, internalizing and externalizing symptoms, and functional impairment. Measures of family functioning included family cohesion, expressiveness, conflict, organization, and household control; parenting measures assessed maternal acceptance and psychological control. Children of mothers with longer current depressive episodes were more likely to have internalizing and externalizing symptoms, with this association being moderated by child gender. Mothers with more lifetime depressive episodes were less likely to use appropriate control in their homes.
PMCID: PMC4086840  PMID: 25013241
Maternal depression; Family functioning; Child adjustment; Gender
2.  Low-dose Transdermal Testosterone Augmentation Therapy Improves Depression Severity in Women 
CNS spectrums  2009;14(12):688-694.
Inadequate response to antidepressant monotherapy in women with major depressive disorder is common. Testosterone administration has been shown to be an effective augmentation therapy in depressed hypogonadal men with selective serotonin reuptake inhibitor-resistant depression. However, the effects of low-dose testosterone as augmentation therapy in women with treatment-resistant depression have not been studied.
Low-dose transdermal testoster one (300 mcg/day, Intrinsa, Procter and Gamble Pharmaceuticals) was administered to nine women with treatment-resistant depression in an 8 week open-label pilot protocol.
There was a statistically significant improvement in mean Montgomery-Asberg Depression Rating Scale (MADRS) scores at 2 weeks, sustained through the 8 week period. Two-thirds of subjects achieved a response to the treatment (decrease in MADRS score of ≥50%) and 33% achieved remission (final MADRS score <10) after 8 weeks of therapy. Mean levels of fatigue, as measured by the MADRS lassitude item, significantly decreased at all time points with a mean 38% decrease from baseline to 8 weeks.
These preliminary pilot data suggest that low-dose transdermal testosterone may be an effective augmentation therapy in women with treatment-resistant depression. Further studies are warranted.
PMCID: PMC4081446  PMID: 20394176
3.  Web-Based Depression Screening and Psychiatric Consultation for College Students: A Feasibility and Acceptability Study 
Background. A steady rise in the prevalence of depression among college students has negatively affected student quality of life. This study investigates the feasibility and acceptability of a Web-based model, including Skype, to screen and provide psychiatric consultation to depressed college students. Methods. Students completed the 9-item Patient Health Questionnaire (PHQ-9) online; those who screened positive (PHQ-9 ≥ 10) or endorsed any level of suicidal ideation were offered Web-based psychiatric consultation using Skype. After the consultation, students filled out a 7-item satisfaction questionnaire to report on the acceptability of this Web-based method. Results. A total of 972 students consented to the online depression screening and 285 screened positive. Of those, 69 students consented and 17 students successfully completed the psychiatric consultation via Skype. Thirteen (76.4%) students found the interview useful in helping them understand their depression. Fifteen (88.2%) students thought that psychologists and psychiatrists could successfully see patients via videoconferencing. Conclusions. Current online technologies can provide depression screening and psychiatric consultation to college students; those who participated reported a positive experience. Future studies will need to address the low levels of participation among college students and attract students who are underserved, as well as use a videoconferencing platform that adequately protects data confidentiality.
PMCID: PMC3985397  PMID: 24799895
4.  Using the Electronic Medical Record to Examine Racial and Ethnic Differences in Depression Diagnosis and Treatment in a Primary Care Population 
We assessed racial and ethnic differences in depression diagnosis and treatment in a primary care population.
A sample of primary care outpatients in 2007 was generated using the electronic medical record (EMR). Patients were considered depressed if their providers billed for depression-related codes; they were considered prescribed antidepressants if any antidepressants were on their medication list. Rates of diagnosis and medication prescription were estimated using a generalized linear model with a Poisson distribution, adjusting for covariates.
In the resulting sample (n=85,790), all minority groups were less likely to be diagnosed with depression as compared to Whites (p<0.05); 11.36% of Whites had a depression diagnosis, as compared to 6.44% of Asian Americans, 7.55% of African Americans, and 10.18% of Latino Americans. Among those with a depression diagnosis (n=11,096), 54.07% of African Americans were prescribed antidepressant medications, as compared to 63.19% Whites (p<0.05); Asian Americans and Latino Americans showed a trend of being less likely to be prescribed antidepressant medications.
Our study illustrates differences in diagnosis and treatment for minority primary care patients, and is innovative in using the EMR to probe these differences. Further research is needed to understand the underlying reasons for these observed differences.
PMCID: PMC3919035  PMID: 24524015
Major Depressive Disorders; Minorities; Electronic Medical Records; Primary Care
5.  Do Menopausal Status and Use of Hormone Therapy Affect Antidepressant Treatment Response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study 
Journal of Women's Health  2013;22(2):121-131.
Menopausal status and use of hormonal contraception or menopausal hormone therapy (HT) may affect treatment response to selective serotonin reuptake inhibitors (SSRIs). This report evaluates whether menopausal status and use of hormonal contraceptives or menopausal HT affect outcome in women treated with citalopram.
In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 896 premenopausal and 544 postmenopausal women were treated with citalopram for 12–14 weeks. Baseline demographic and clinical characteristics were used in adjusted analysis of the effect of menopausal status and use of hormonal contraceptives or menopausal HT on outcomes. Remission was defined as final Hamilton Rating Scale for Depression-17 (HRSD17) ≤7 or Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) score ≤5 and response as ≥50% decrease from the baseline QIDS-SR16 score.
Premenopausal and postmenopausal women differed in multiple clinical and demographic baseline variables but did not differ in response or remission rates. Premenopausal women taking hormonal contraceptives had significantly greater unadjusted remission rates on the HRSD17 and the QIDS-SR16 than women not taking contraception. Response and remission rates were not different between postmenopausal women taking vs. not taking HT. Adjusted results showed no significant difference in any outcome measure across menopause status in women who were not taking contraception/HT. There were no significant differences in adjusted results across HT status in premenopausal or postmenopausal women.
In this study, citalopram treatment outcome was not affected by menopausal status. Hormonal contraceptives and HT also did not affect probability of good outcome.
PMCID: PMC3613168  PMID: 23398127
6.  Psychosocial stressors and the prognosis of major depression: a test of Axis IV 
Psychological medicine  2012;43(2):303-316.
Axis IV is for reporting “psychosocial and environmental problems that may affect the diagnosis, treatment, and prognosis of mental disorders.” No studies have examined the prognostic value of Axis IV in DSM-IV.
We analyzed data from 2,497 participants in the National Epidemiologic Survey on Alcohol and Related Conditions with major depressive episode (MDE). We hypothesized that psychosocial stressors predict a poor prognosis of MDE. Secondarily, we hypothesized that psychosocial stressors predict a poor prognosis of anxiety and substance use disorders. Stressors were defined according to DSM-IV’s taxonomy, and empirically using latent class analysis.
Primary support group problems, occupational problems, and childhood adversity increased the risks of depressive episodes and suicidal ideation by 20–30%. Associations of the empirically derived classes of stressors with depression were larger in magnitude. Economic stressors conferred a 1.5-fold increase in risk for a depressive episode (CI=1.2–1.9); financial and interpersonal instability conferred a 1.3-fold increased risk of recurrent depression (CI=1.1–1.6). These two classes of stressors also predicted the recurrence of anxiety and substance use disorders. Stressors were not related to suicidal ideation independent from depression severity.
Psychosocial and environmental problems are associated with the prognosis of MDE and other Axis I disorders. Though DSM-IV’s taxonomy of stressors stands to be improved, these results provide empirical support for the prognostic value of Axis IV. Future work is needed to determine the reliability of Axis IV assessments in clinical practice, and the usefulness of this information to improving the clinical course of mental disorders.
PMCID: PMC3721739  PMID: 22640506
7.  Cross-Disorder Genomewide Analysis of Schizophrenia, Bipolar Disorder, and Depression 
The American journal of psychiatry  2010;167(10):10.1176/appi.ajp.2010.09091335.
Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). The objective of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders.
We combined GWAS data from three large effectiveness studies of SCZ (CATIE, genotyped n = 741), BPD (STEP-BD, n = 1575) and MDD (STAR*D, n= 1938) and psychiatrically-screened controls (NIMH-GI controls, n = 1204). We applied a two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups followed by a model selection step to identify the best-fitting model of allelic effects across disorders.
The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218, p = 3.93 × 10−8), with the best-fitting model indicating that the effect is specific to bipolar II disorder. We also observed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries including variants in NPAS3 that showed pleiotropic effects across SCZ, BPD, and MDD.
This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although we do not detect genomewide significant evidence of cross-disorder effects, our study provides evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrates an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.
PMCID: PMC3880556  PMID: 20713499
8.  Cognitive Therapy Alone and in Combination with Antidepressants for Anxious Depression: A STAR*D Report 
Journal of affective disorders  2012;142(1-3):213-218.
Anxious depression, defined as MDD with high levels of anxiety, has been associated with lower rates of antidepressant response and remission as well as greater chronicity, suicidality and antidepressant side-effect burden. The primary aim of this study was to assess the effectiveness of cognitive therapy (CT) alone or in combination with medications for anxious versus non-anxious depression.
We assessed the STAR*D study participants who were partial or non-responders to citalopram. Subjects were then either switched (n = 696) to a new antidepressant or to CT alone, or they were kept on citalopram and augmented (n = 577) with another antidepressant or CT. We compared response and remission rates of those who met criteria for anxious depression to those who did not across treatment conditions.
Those with anxious depression had significantly lower remission rates based on the QIDS, whether assigned to switch or augmentation, compared to those with non-anxious depression. Those with anxious depression, compared to those without, had significantly lower response rates based on the QIDS only in the switch group. There was no significant interaction between anxious depression and treatment assignment.
Limitations include the use of citalopram as the only Level 1 pharmacotherapy and medication augmentation option, depression-focused CT rather than anxiety-focused CT, and focus on acute treatment outcomes.
Individuals with anxious depression appear to experience higher risk of poorer outcome following pharmacotherapy and/or CT after an initial course of SSRI, and continued efforts to target this challenging form of depression are needed.
PMCID: PMC3483355  PMID: 22877961
anxious depression; MDD; CT; psychosocial interventions; STAR*D
9.  What Are the Clinical Implications of New Onset or Worsening Anxiety During the First Two Weeks of SSRI Treatment for Depression? 
Depression and anxiety  2011;29(2):10.1002/da.20917.
To evaluate the prevalence of new onset or worsening of anxiety symptoms, as well as their clinical implications, during the first two weeks of Selective Serotonin Reuptake Inhibitor (SSRI) pharmacotherapy for depression.
Adult outpatients with non-psychotic major depressive disorder were enrolled in an 8-week acute phase SSRI treatment trial at 15 clinical sites across the US. Worsening anxiety was defined as a greater than 2 point increase on the Beck Anxiety Inventory (BAI) between baseline and Week 2. New onset of anxiety symptoms was ascribed when the BAI baseline rating was 0 and the Week 2 value was greater or equal to 2 points on the BAI.
Overall, after two weeks of treatment, 48.8% (98 of 201 participants) reported improvement in anxiety symptoms, 36.3% (73 of 201) reported minimal symptom change, and 14.9% (30 of 201) reported worsening of anxiety symptoms. No association was found between change in anxiety symptoms within the first two weeks and change in depressive symptoms or remission at the end of 8 weeks of treatment. For participants with clinically meaningful anxiety symptoms at baseline, however, worsening of anxiety during the first two weeks of treatment was associated with worsening depressive symptoms by 8 weeks (p = .054).
The trajectory of anxiety symptom change early in SSRI treatment is an important indicator of eventual outcome for outpatients with major depression and baseline anxiety symptoms.
PMCID: PMC3860362  PMID: 22147631
anxiety; change; depression; SSRI; outcome
10.  Open-Label Placebo for Major Depressive Disorder: A Pilot Randomized Controlled Trial 
Psychotherapy and psychosomatics  2012;81(5):10.1159/000337053.
PMCID: PMC3813004  PMID: 22854752
Randomized Controlled Trial; Major Depressive Disorder; Placebo
11.  Genome-Wide Association Study of Suicide Attempts in Mood Disorder Patients 
The American journal of psychiatry  2010;167(12):1499-1507.
Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.
The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.
Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.
The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.
PMCID: PMC3795390  PMID: 21041247
12.  A Randomized, Controlled, Pilot Study of Acamprosate Added to Escitalopram in Adults With Major Depressive Disorder and Alcohol Use Disorder 
We sought to examine the efficacy and safety of acamprosate augmentation of escitalopram in patients with concurrent major depressive disorder (MDD) and alcohol use disorders. Twenty-three adults (43% female; mean ± SD age, 46 ± 14 years) were enrolled and received 12 weeks of treatment with psychosocial support; escitalopram, 10 to 30 mg/d; and either acamprosate, 2000 mg/d (n = 12), or identical placebo (n = 11). Outcomes included change in clinician ratings of depressive symptoms, MDD response and remission rates, changes in frequency and intensity of alcohol use, retention rates, and adverse events. Twelve subjects (acamprosate, n = 7; placebo, n = 5) completed the study. There was significant mean reduction in ratings of depressive symptoms from baseline in both treatment arms (P < 0.05), with no significant difference between the groups. Those in the acamprosate group had a 50% MDD response rate and a 42% remission rate, whereas those in the placebo arm had a 36% response and remission rate (not significant). Those assigned to acamprosate had significant reduction in number of drinks per week and drinks per month during the trial, whereas those assigned to placebo demonstrated no significant change in any alcohol use parameter, but the between-group difference was not significant. There were no significant associations between change in depressive symptoms and change in alcohol use. Attrition rates did not differ significantly between the 2 arms. Acamprosate added to escitalopram in adults with MDD and alcohol use disorders was associated with reduction in the frequency of alcohol use. The present study was not powered to detect superiority versus placebo. Further study in a larger sample is warranted.
PMCID: PMC3794470  PMID: 23131884
acamprosate; alcohol use disorder; AUD; depression; MDD; escitalopram
13.  Association Between Bipolar Spectrum Features and Treatment Outcomes in Outpatients With Major Depressive Disorder 
Archives of general psychiatry  2010;68(4):351-360.
It has been suggested that patients with major depressive disorder (MDD) who display pretreatment features suggestive of bipolar disorder or bipolar spectrum features might have poorer treatment outcomes.
To assess the association between bipolar spectrum features and antidepressant treatment outcome in MDD.
Open treatment followed by sequential randomized controlled trials.
Primary and specialty psychiatric outpatient centers in the United States.
Male and female outpatients aged 18 to 75 years with a DSM-IV diagnosis of nonpsychotic MDD who participated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.
Open treatment with citalopram followed by up to 3 sequential next-step treatments.
Main Outcome Measures
Number of treatment levels required to reach protocol-defined remission, as well as failure to return for the postbaseline visit, loss to follow-up, and psychiatric adverse events. For this secondary analysis, putative bipolar spectrum features, including items on the mania and psychosis subscales of the Psychiatric Diagnosis Screening Questionnaire, were examined for association with treatment outcomes.
Of the 4041 subjects who entered the study, 1198 (30.0%) endorsed at least 1 item on the psychosis scale and 1524 (38.1%) described at least 1 recent manic-like/hypomaniclike symptom. Irritability and psychotic-like symptoms at entry were significantly associated with poorer outcomes across up to 4 treatment levels, as were shorter episodes and some neurovegetative symptoms of depression. However, other indicators of bipolar diathesis including recent maniclike symptoms and family history of bipolar disorder as well as summary measures of bipolar spectrum features were not associated with treatment resistance.
Self-reported psychoticlike symptoms were common in a community sample of outpatients with MDD and strongly associated with poorer outcomes. Overall, the data do not support the hypothesis that unrecognized bipolar spectrum illness contributes substantially to antidepressant treatment resistance.
PMCID: PMC3794668  PMID: 21135313
14.  Factors that distinguish college students with depressive symptoms with and without suicidal thoughts 
Suicide among college students is a significant public health concern. Although suicidality is linked to depression, not all depressed college students experience suicidal ideation (SI). The primary aim of this study was to determine potential factors that may distinguish college students with depressive symptoms with and without SI.
A total of 287 undergraduate college students with substantial depressive symptoms (Beck Depression Inventory [BDI] total score >13) with and without SI were compared across psychiatric and functional outcome variables. Independent sample t tests were conducted for each outcome variable using the suicide item of the BDI as a dichotomous (ie, zero vs nonzero score) grouping variable.
Relative to students with substantial depressive symptoms without SI, those with SI were more symptomatic overall, having significantly higher levels of depressive symptoms, hopelessness, and anxiety. However, contrary to our expectations, nonsuicidal and suicidal students did not differ on measures of everyday functioning (ie, cognitive and physical functioning and grade point average).
Our findings suggest that SI among college students is associated with increased subjective distress but may not adversely impact physical or cognitive functioning or academic performance.
PMCID: PMC3791316  PMID: 23376869
suicide; depression; college students; anxiety; undergraduate; hopelessness
15.  Compulsive use of alcohol among college students 
Psychiatry research  2012;205(0):95-102.
Among college students alcohol consumption is associated with other high-risk behaviors that can lead to short- and long-term negative health consequences. Identification of college students consuming alcohol who are at high risk for problems may have important public health implications. This study examines the ability of the CHQ compulsive use of alcohol item to detect high-risk behaviors relative to other screening measures and its association with different dimensions of compulsive drinking. Three hundred thirty-two college students completed measures on compulsive drinking and hazardous behaviors. Results showed that among male students the CHQ compulsive use of alcohol item was not sensitive to detect hazardous alcohol consumption but co-occurred with the use of illicit drugs. Among female students it was sensitive to detect heavy drinking but not alcohol or drug problems. Among college students compulsive use of alcohol corresponds to an urge to consume alcohol that may be associated with use of illicit drugs in male students, with heavy drinking in female students and with substance use problems. This study suggest that the CHQ compulsive use of alcohol item should not be used as a stand-alone screening for alcohol or drug problems but it could be considered a marker for at-risk behaviors.
PMCID: PMC3791317  PMID: 22951374
College students; Compulsive drinking; Risky behaviors; Alcohol; Drug use
16.  Antidepressant Response in Patients With Major Depression Exposed to NSAIDs: A Pharmacovigilance Study 
The American journal of psychiatry  2012;169(10):1065-1072.
It has been suggested that there is a mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with antidepressant response, and poorer outcomes among NSAID-treated patients were reported in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. To attempt to confirm this association in an independent population-based treatment cohort and explore potential confounding variables, the authors examined use of NSAIDs and related medications among 1,528 outpatients in a New England health care system.
Treatment outcomes were classified using a validated machine learning tool applied to electronic medical records. Logistic regression was used to examine the association between medication exposure and treatment outcomes, adjusted for potential confounding variables. To further elucidate confounding and treatment specificity of the observed effects, data from the STAR*D study were reanalyzed.
NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio=1.55, 95% CI=1.21–2.00). This association was apparent in the NSAIDs-only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and salicylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables.
These results support an association between NSAID use and poorer antidepressant outcomes in major depressive disorder but indicate that some of the observed effect may be a result of confounding.
PMCID: PMC3787520  PMID: 23032386
17.  Do Suicidal Thoughts or Behaviors Recur During a Second Antidepressant Treatment Trial? 
The Journal of clinical psychiatry  2012;73(11):1439-1442.
A subset of patients undergoing initial antidepressant treatment experience worsening of symptoms, including thoughts of suicide or suicidal behavior. The present study explores whether this subset of patients is also more likely to experience recurrence or worsening of these symptoms during a second treatment trial with a different antidepressant.
We examined data collected between July 2001 and September 2006 from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a multicenter effectiveness study of outpatients with major depressive disorder diagnosed by a DSM-IV checklist. In that study, subjects who did not remit with citalopram treatment were randomized among next-step treatment options. The main outcome measure for this post hoc analysis, presence of suicidal thoughts and behaviors, was assessed using the suicide item on the 16-item Quick Inventory of Depressive Symptomatology—Self-Rated. Logistic regression was used to examine association between emergence or worsening of these symptoms with the first-step (level 1) citalopram treatment and emergence or worsening with next-step (level 2) pharmacologic or psychosocial treatment, including augmentation with bupropion or buspirone; switch to sertraline, venlafaxine, or bupropion; or addition of or switch to cognitive therapy.
Of 1,240 subjects entering level 2 with a score less than 3 on the suicide item, 102 (8.2%) experienced emergence or worsening of suicidal thoughts or behaviors. Emergence or worsening at level 1 was strongly associated with reemergence or worsening at level 2 (crude OR=4.00 [95% CI, 2.45–6.51], adjusted OR=2.95 [95% CI, 1.76–4.96]). Overall magnitude of risk was similar among next-step pharmacologic augmentation versus switching.
These results suggest that individuals who experience emergence or worsening of suicidal thoughts or behaviors with one antidepressant treatment may warrant closer follow-up during the next-step treatment, as these symptoms may recur regardless of which modality is selected.
PMCID: PMC3787539  PMID: 23059018
18.  Association of a Polymorphism Near CREB1 With Differential Aversion Processing in the Insula of Healthy Participants 
Archives of general psychiatry  2008;65(8):882-892.
Previous functional neuroimaging studies have identified a network of brain regions that process aversive stimuli, including anger. A polymorphism near the cyclic adenosine monophosphate response element binding protein gene (CREB1) has recently been associated with greater self-reported effort at anger control as well as risk for antidepressant treatment–emergent suicidality in men with major depressive disorder, but its functional effects have not been studied.
To determine whether this genetic variant is associated with altered brain processing of and behavioral avoidance responses to angry facial expressions.
Design and Participants
A total of 28 white participants (mean age, 29.2 years; 13 women) were screened using the Structured Clinical Interview for DSM-IV to exclude any lifetime Axis I psychiatric disorder and were genotyped for rs4675690, a single-nucleotide polymorphism near CREB1.
Main Outcome Measures
Blood oxygenation level–dependent signal by functional magnetic resonance imaging in the amygdala, insula, anterior cingulate, and orbitofrontal cortex during passive viewing of photographs of faces with emotional expressions. To measure approach and avoidance responses to anger, an off-line key-press task that traded effort for viewing time assessed valuation of angry faces compared with other expressions.
The CREB1-linked single-nucleotide polymorphism was associated with significant differential activation in an extended neural network responding to angry and other facial expressions. The CREB1-associated insular activation was coincident with activation associated with behavioral avoidance of angry faces.
A polymorphism near CREB1 is associated with responsiveness to angry faces in a brain network implicated in processing aversion. Coincident activation in the left insula is further associated with behavioral avoidance of these stimuli.
PMCID: PMC3782742  PMID: 18678793
19.  The Quick Inventory of Depressive Symptomatology, Clinician Rated and Self-report 
This study aimed to investigate the psychometric properties of the Chinese translations of the Quick Inventory of Depressive Symptomatology (QIDS16), including the Clinician-Rated (QIDS-C16), Self-report (QIDS-SR16), and Interactive Voice Response (QIDS-SR-IVR16) formats. Thirty depressed Chinese Americans were assessed with Chinese translations of the QIDS-SR16, QIDS-SR-IVR16, and QIDS-C16. Cronbach alpha estimates of internal scale consistency on the QIDS-SR16, QIDS-SR-IVR16, and QIDS-C16 were 0.70, 0.74, and 0.79, respectively. Intercorrelations among the measures were QIDS-SR16 and QIDS-SR-IVR16, r = 0.79; QIDS-SR16 and QIDS-C16, r = 0.61; and QIDS-SR-IVR16 and QIDS-C16, r = 0.69 (all p values < 0.01). The areas under the curve for the receiver operating characteristics of the QIDS-SR16 and QIDS-SR-IVR16 were 0.78 (95% confidence interval, 0.61–0.95) and 0.81 (95% confidence interval, 0.65–0.96), respectively. The respective screening sensitivities/specificities were 0.73/0.74 and 0.86/0.58. The Chinese translations of the QIDS16 have adequate psychometric properties and may be useful tools for depression screening.
PMCID: PMC3762496  PMID: 22850307
Depression; Chinese; psychometrics; severity of illness index; psychiatric status rating scales
20.  Brain fMRI Responses to Smoking-Related Images Prior to and During Extended Smoking Abstinence 
Reactivity to smoking-related cues may play a role in the maintenance of smoking behavior and may change depending on smoking status. Whether smoking cue-related functional MRI (fMRI) reactivity differs between active smoking and extended smoking abstinence states currently is unknown.
We used fMRI to measure brain reactivity in response to smoking-related versus neutral images in 13 tobacco-dependent subjects prior to a smoking cessation attempt and again during extended smoking abstinence (52 ± 11 days) aided by nicotine replacement therapy.
Pre-quit smoking cue induced fMRI activity patterns paralleled those reported in prior smoking cue reactivity fMRI studies. Greater fMRI activity was detected during extended smoking abstinence than during the pre-quit assessment subcortically in the caudate nucleus and cortically in prefrontal (BA 6, 9, 44, 46), primary somatosensory (BA 1,2,3), temporal (BA 22, 41, 42), parietal (BA 7, 40) anterior cingulate (BA 24, 32), and posterior cingulate (BA 31) cortex.
These data suggest that during extended smoking abstinence, fMRI reactivity to smoking versus neutral stimuli persists in brain areas involved in attention, somatosensory processing, motor planning, and conditioned cue responding. In some brain regions, fMRI smoking cue reactivity is increased during extended smoking abstinence in comparison to the pre-quit state, which may contribute to persisting relapse vulnerability.
PMCID: PMC3742373  PMID: 19968401
abstinence; addiction; caudate nucleus; fMRI; nicotine
21.  A Double-Blind, Placebo-Controlled Trial of the NMDA Glycine Site Antagonist, GW468816, for Prevention of Relapse to Smoking in Females 
Relapse to smoking is common after initial abstinence with pharmacotherapy and behavioral support and represents a major clinical challenge. Although mechanisms underlying relapse to smoking have not been elucidated, preclinical studies suggest that glutamate receptors may be involved. We sought to test a selective antagonist of the glycine coag-onist site on the glutamate N-methyl-d-aspartate receptor, GW468816, for prevention of relapse in recently abstinent smokers. To do so, we enrolled 264 healthy female smokers in an open 8-week smoking cessation intervention with behavioral therapy and a standard dose of transdermal nicotine replacement therapy with taper and additional gum or lozenge as needed for nicotine withdrawal symptoms. Ninety-eight participants achieved 7-day point prevalence abstinence and were randomized into a 5-week double-blind, placebo-controlled, relapse-prevention trial of GW468816 (200 mg/d) and then followed for 60 days after randomization. There was no effect of treatment on abstinence rates at the end of treatment (χ2 [1, n = 96] = 0.168, p = 0.838), on the rates of relapse (χ2 [1, n = 98] = 0.031, p = 1.000) or lapse (χ2 [1, n = 62] = 0.802, p = 0.423), or on time to relapse (χ2 [1, n = 98) = 0.001, p = 0.972). No significant relationships were detected between plasma GW468816 concentrations and abstinence, time to relapse, or self-reported craving. In conclusion, despite promising preclinical data that support the use of a selective NMDA glycine site antagonist for prevention of relapse to smoking, we observed no effect of GW468816 on relapse or lapse rates, time to relapse, or craving compared to placebo.
PMCID: PMC3741043  PMID: 21869693
nicotine; smoking cessation; NMDA; glutamate; relapse prevention; glycine
22.  Bereavement and the Diagnosis of Major Depressive Episode 
Bereavement-related depression is excluded from a diagnosis of major depressive episode (MDE) in DSM-IV unless the syndrome is prolonged or complicated. The objective of this study is to assess the validity of the bereavement exclusion by comparing characteristics of bereavement-related episodes that are excluded from a diagnosis, and bereavement-related episodes that qualify for a diagnosis (complicated bereavement), to MDE.
We used data from two waves of the National Epidemiologic Survey on Alcohol and Related Conditions to compare bereavement-excluded depression and complicated bereavement to MDE with respect to indicators of pre-existing risk for psychopathology (antecedent indicators) and indicators of disorder severity (consequent indicators).
Compared to individuals with MDE, individuals with bereavement-excluded depression had lower risks of pre-existing psychiatric disorders (e.g., 0.44 lower odds of social phobia, P=0.006), fewer depressive episodes (recurrence rate 0.37 times lower, P<0.001), less impairment, an 0.18 times lower odds of seeking treatment (P<0.001), and a lower risk of psychiatric disorders during a 3-year follow-up period. Unexpectedly, this same pattern of differences was observed between individuals with complicated bereavement and MDE.
Despite the presence of a clinically significant depressive episode, bereavement-excluded depression is in many ways less indicative of psychopathology than MDE. However, complicated bereavement was more similar to bereavement-excluded depression than to MDE. We therefore question whether the DSM-IV criteria validly distinguish between non-disordered loss reactions (bereavement-excluded depression), pathological loss reactions (complicated bereavement), and non-loss related MDE.
PMCID: PMC3721753  PMID: 21903020
Depression; bereavement; validity
23.  Assessing anxious features in depressed outpatients 
Both the 17-item Hamilton Rating Scale for Depression (HRSD17) and 30-item Inventory of Depressive Symptomatology – Clinician-rated (IDS-C30) contain a subscale that assesses anxious symptoms. We used classical test theory and item response theory methods to assess and compare the psychometric properties of the two anxiety subscales (HRSDANX and IDS-CANX) in a large sample (N = 3453) of outpatients with non-psychotic major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Approximately 48% of evaluable participants had at least one concurrent anxiety disorder by the self-report Psychiatric Diagnostic Screening Questionnaire (PDSQ). The HRSDANX and IDS-CANX were highly correlated (r = 0.75) and both had moderate internal consistency given their limited number of items (HRSDANX Cronbach’s alpha = 0.48; IDS-CANX Cronbach’s alpha = 0.58). The optimal threshold for ascribing the presence/absence of anxious features was found at a total score of eight or nine for the HRSDANX and seven or eight for the IDS-CANX. It would seem beneficial to delete item 17 (loss of insight) from the HRSDANX as it negatively correlated with the scale’s total score. Both the HRSDANX and IDS-CANX subscales have acceptable psychometric properties and can be used to identify anxious features for clinical or research purposes.
PMCID: PMC3708141  PMID: 22057975
depression; anxiety; rating scales; STAR*D; measurement-based care
24.  The Treatment of Depressed Chinese Americans Using Qigong in a Health Care Setting: A Pilot Study 
Background. This pilot study examined the feasibility and efficacy of providing Qigong treatment in a health center to Chinese Americans with major depressive disorder (MDD). Methods. Fourteen Chinese Americans with MDD were enrolled, and they received a 12-week Qigong intervention. The key outcome measurement was the 17-item Hamilton Rating Scale for Depression (HAM-D17); the Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I), the Quality of Life Enjoyment and Satisfaction Questionnaire, Short Form (Q-LES-Q-SF), and the Multidimensional Scale of Perceived Social Support (MSPSS) were also administered. Positive response was defined as a decrease of 50% or more on the HAM-D17, and remission was defined as HAM-D17 ≤ 7. Patients' outcome measurements were compared before and after the Qigong intervention. Results. Participants (N = 14) were 64% female, with a mean age of 53 (±14). A 71% of participants completed the intervention. The Qigong intervention resulted in a positive treatment-response rate of 60% and a remission rate of 40% and statistically significant improvement, as measured by the HAM-D17, CGI-S, CGI-I, Q-LES-Q-SF, and the family support subscale of the MSPSS. Conclusions. The Qigong intervention provided at a health care setting for the treatment of primary care patients with MDD is feasible. Further studies with larger sample sizes are warranted.
PMCID: PMC3639645  PMID: 23690836
25.  Baseline depression severity as a predictor of single and combination antidepressant treatment outcome: Results from the CO-MED Trial 
European Neuropsychopharmacology  2011;22(3):183-199.
The objective of this manuscript is to report associations between baseline depressive severity and (1) baseline sociodemographic and clinical characteristics, (2) treatment outcomes, and (3) differential outcomes for three treatment groups. Six hundred and sixty-five outpatients with nonpsychotic, major depressive disorder were prospectively randomized to treatment with either a selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) or one of two antidepressant medication combinations (bupropion-sustained release plus escitalopram, or venlafaxine-extended release plus mirtazapine). For purposes of these analyses, participants were divided into four groups based on baseline severity by the 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16) total score: mild (0–10) [N=81], moderate (11–15) [N=238], severe (16–20) [N=260] and very severe (21–27) [N=67]. Treatment outcomes at 12 and 28 weeks were compared among the four severity groups. A history of childhood neglect and/or abuse was strongly associated with the severity of adult depression (1/2 of participants in the very severy group versus 1/5–1/4 of those in the mild group reported abuse and/or neglect). The degree of suicidality (e.g., 15/.4% of the very severe group ever attempted suicide versus none in the mild group), the number of suicide attempts (e.g., mean of .41 +/− 1.99 suicide attempts in the severe group versus o.o +/−0.0 in the mild group) and severity of suicidality (e.g., 9.2% of participants in very severe group had a plan or made a gesture versus 5.6% in moderate group and none in the mild group) were increased in more severe groups. Participants with a greater baseline depressive severity reported significantly more psychiatric comorbitities (e..g. [at p < 0.05] increased rates of agoraphobia, bulimia, generalized anxiety, hypocondriasis, panic disorder, post-traumatic stress disorder, social phobia and somatoform disorder, with 23.9 % of participants in the very severe group having reported four or more psychiatric disorders versus 1.2% of the mild group). Combination medication treatments were no more effective in treating severe depressions than was SSRI monotherapy. Remission (61.7% of participants in the mild group achieved remission versus 28.4% in the very severe group) is more difficult to achieve in more severe groups than is response (48.8% of participants in the mild group achieved response versus 58.2% in the very severe group) (p < 0.03) . These data may help us to understand the impact of baseline features on antidepressant medication effectiveness and to inform the personalization of depression treatment across the spectrum of depressive severity.
PMCID: PMC3273676  PMID: 21920711
Depression; abuse; suicide; combination treatment severity; response; remission

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