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1.  Rare Copy Number Variation in Treatment-Resistant Major Depressive Disorder 
Biological psychiatry  2014;76(7):536-541.
While antidepressant treatment response appears to be partially heritable, no consistent genetic associations have been identified. Large, rare copy number variants (CNVs) play a role in other neuropsychiatric diseases, so we assessed their association with treatment-resistant depression (TRD).
We analyzed data from two genome-wide association studies comprising 1263 Caucasian patients with major depressive disorder. One was drawn from a large health system by applying natural language processing to electronic health records (i2b2 cohort). The second consisted of a multicenter study of sequential antidepressant treatments, Sequenced Treatment Alternatives to Relieve Depression. The Birdsuite package was used to identify rare deletions and duplications. Individuals without symptomatic remission, despite two antidepressant treatment trials, were contrasted with those who remitted with a first treatment trial.
CNV data were derived for 778 subjects in the i2b2 cohort, including 300 subjects (37%) with TRD, and 485 subjects in Sequenced Treatment Alternatives to Relieve Depression cohort, including 152 (31%) with TRD. CNV burden analyses identified modest enrichment of duplications in cases (empirical p = .04 for duplications of 100–200 kilobase) and a particular deletion region spanning gene PABPC4L (empirical p = .02, 6 cases: 0 controls). Pathway analysis suggested enrichment of CNVs intersecting genes regulating actin cytoskeleton. However, none of these associations survived genome-wide correction.
Contribution of rare CNVs to TRD appears to be modest, individually or in aggregate. The electronic health record-based methodology demonstrated here should facilitate collection of larger TRD cohorts necessary to further characterize these effects.
PMCID: PMC4104153  PMID: 24529801
Antidepressant; copy number; deletion; duplication; pharmacogenetic; pharmacogenomic; rare genetic variation
2.  Relationship Between Obesity and Depression: Characteristics and Treatment Outcomes with Antidepressant Medication 
Psychosomatic medicine  2013;75(9):863-872.
Obesity and Major Depressive Disorder (MDD) often co-occur. However, differences between obese and normal-weight depressed patients and the moderating effect of obesity on antidepressant treatment outcome have not been well studied.
662 subjects in the COmbining Medications to Enhance Depression Outcomes (COMED) were randomized to treatment with escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine for a 12 week primary treatment phase and 16 week follow-up. Body Mass Index (BMI) was calculated at baseline. Subjects were divided into BMI classes according to World Health Organization criteria: 1) normal (and low) weight (NW), 2) overweight (OW), 3) obese I (OB1) and 4) obese II+ (OB2). Clinical characteristics were compared using Chi-squared or Kruskall-Wallis testing. Outcomes were assessed using a repeated effects model, unadjusted and adjusted for baseline variables differing across BMI classes.
31.4% of the subjects were normal weight; 46.2% were obese. Higher BMI was associated with greater medical illness (p<0.001), social phobia (p=0.003) and bulimia (p=0.026). Lower BMI was associated with higher rates of Post Traumatic Stress Disorder (p=0.002) and drug abuse. Treatment outcomes, including remission, did not differ across classes. However, lower BMI was associated with more frequent (p=0.024, unadjusted, 0.053 adjusted) and more severe (p=0.008 unadjusted, 0.053 adjusted) side effects.
We found a high rate of obesity compared to the general population and significant differences in presentation and comorbidity, but not medication use and antidepressant outcomes, in subjects across BMI classes. Lower BMI classes had higher rates of comorbidities associated with poor outcome, which may have obscured outcome differences.
Trial Registration Identifier: NCT 00270647
PMCID: PMC3905462  PMID: 24163386
Depression; Obesity; Treatment Resistance
4.  Bioavailability of S-Adenosyl Methionine and Impact on Response in a Randomized Controlled Trial in Major Depressive Disorder 
To characterize the impact of S-adenosylmethionine (SAMe) on homocysteine, and potential risk of adverse cardiovascular effects, by examining plasma levels of SAMe, S-adenosylhomocysteine (SAH), total homocysteine (tHCY), methionine (MET), and 5-methyltetrahydrofolate (5-MHTF) in 35 of 73 patients from a 6-week double-blind randomized trial of SAMe augmentation in serotonin-reuptake inhibitor partial responders with DSM-IV major depressive disorder (MDD), published in 2010.
Subjects were randomized from 6/4/2004-8/8/2008 to adjunctive placebo or SAMe 800-1600 mg/day for 6 weeks. Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm (by paired t-test) and between treatment arms (by independent samples t-test). Univariate analysis of variance and Fisher’s Protected Least Significant Difference were carried out to compare post-treatment levels of each one-carbon cycle intermediate. Secondary outcome measures included associations between clinical improvement and change in plasma intermediates, examined by linear regression (for change in HAM-D) and logistic regression (for response or remission).
We found significant differences in pre-treatment plasma levels of tHCY (p=0.03) between the SAMe and placebo arms. Following 6 weeks of treatment, plasma SAMe (p=0.002) and SAH (p<0.0001) levels increased significantly in the SAMe arm; no intermediates in the placebo group changed significantly. Post-treatment plasma SAMe (p=0.0035), SAH (P<0.0001), and tHCY (p=0.0016) differed significantly between the SAMe and placebo groups. No significant associations were found between plasma intermediate levels and clinical improvement, response, or remission.
Despite concerns about the impact that SAMe therapy may have on homocysteine, and risk of adverse cardiovascular effects, the lack of significant increase in tHCY after treatment suggests that no toxic effects from SAMe should be expected. Our findings, however, have some significant limitations and should be interpreted with caution.
PMCID: PMC4156851  PMID: 22687580
SAMe; S-adenosylmethionine; bioavailability; depression; homocysteine; methionine; methyltetrahydrofolate
5.  Differential Impact of Isolated Psychotic Symptoms on Treatment Outcome of Major Depressive Disorder in the STAR*D cohort of Whites, Blacks and Latinos 
Journal of affective disorders  2013;150(2):578-584.
To determine whether isolated psychotic symptoms are more likely to be endorsed by depressed Latinos as opposed to other ethnic-racial groups; whether these symptoms affect Latinos similarly to other ethnic-racial groups in terms of treatment response; and whether they are more likely to be associated with anxiety disorders in depressed Latinos.
We analyzed data from STAR*D subjects who self identified as White, Black, or Latino. Rates of isolated psychotic symptoms were assessed by the self-rated Psychiatric Diagnostic Screening Questionnaire (PDSQ) and compared between ethnic-racial groups. Depressive remission outcomes were compared within each ethnic-racial group between subjects who endorsed psychotic symptoms versus no psychotic symptoms. Associations between isolated psychotic symptoms and anxiety disorders were also examined.
Among 2,597 eligible subjects with at least one post-baseline assessment and available PDSQ data excluding first-rank symptoms, the prevalence of auditory-visual hallucination was 2.5% in Whites (n=49 /1,928), 11.3% in Blacks (n=45 /398) 6.3% in Latinos (n=17 /270) (χ2=64.9; df=2; p<.001). Prevalence of paranoid ideation was 15.5% in Whites (n=299 /1927), 31.5% in Blacks (n=126 /400), and 21.1% in Latinos (n=57 /270) (χ2=57.3; df=2; p<.001). Among Whites and Blacks but not Latinos, depressive remission rates were worse in subjects with auditory-visual hallucinations compared to those without them. Paranoid ideation had a significant negative impact on remission in Whites only. In all ethnic-racial groups, a significant association was found between auditory-visual hallucinations and PTSD and panic disorder.
the STAR*D study did not include any structured clinician-based assessment of psychotic symptoms.
Latinos do not appear to have worse outcomes when treated for MDD with auditory-visual hallucinations, differently from Whites and Blacks.
PMCID: PMC3749257  PMID: 23489398
Latinos; Hispanic; Major Depressive Disorder; Psychosis-like Symptoms; Antidepressants; Remission
7.  Effectiveness of the Relaxation Response-Based Group Intervention for Treating Depressed Chinese American Immigrants: A Pilot Study 
Background: This study examined the feasibility, safety and efficacy of an 8-week Relaxation Response (RR)-based group. Methods: Twenty-two depressed Chinese American immigrants were recruited. Outcomes measures were response and remission rates, the Hamilton Rating Scale for Depression, Clinical Global Impressions Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and the Multidimensional Scale of Perceived Social Support Scale. Results: Participants (N = 22) were 82% female, mean age was 53 (±12). After intervention, completers (N = 15) showed a 40% response rate and a 27% remission rate, and statistically significant improvement in most outcome measures. Discussion: The RR-based group is feasible and safe in treating Chinese American immigrants with depression.
PMCID: PMC4199014  PMID: 25198683
depression; Chinese; relaxation response; mind-body; group intervention
Depression and anxiety  2013;30(9):10.1002/da.22064.
Sleep disturbance (SD) has complex associations with depression, both preceding and following the onset and recurrence of depression. We hypothesized that students with depressive symptoms with SD would demonstrate a greater burden of comorbid psychiatric symptoms and functional impairment compared to students with depressive symptoms without SD.
During a mental health screening, 287 undergraduate students endorsed symptoms of depression (Beck Depression Inventory [BDI] ≥ 13) and filled out the following self-report measures: demographic questionnaire, BDI, Anxiety Symptom Questionnaire—intensity and frequency (ASQ), Beck Hopelessness Scale (BHS), Beck Anxiety Inventory (BAI), Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ), and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ). SD was measured using the BDI sleep item #16 dichotomized (score 0: no SD; or score > 0: some SD).
Students with depressive symptoms and SD (n = 220), compared to those without SD (n = 67), endorsed significantly more intense and frequent anxiety and poorer cognitive and physical functioning. Students with depressive symptoms with and without SD did not significantly differ in depressive severity, hopelessness, or quality of life.
College students with depressive symptoms with SD may experience a greater burden of comorbid anxiety symptoms and hyperarousal, and may have impairments in functioning, compared to students with depressive symptoms without SD. These findings require replication. Depression and Anxiety 00:1–8, 2013.
PMCID: PMC3791314  PMID: 23681944
sleep; depression; anxiety; hopelessness; functioning; quality of life; college students; mental health screening; hyperarousal
9.  Combined MI + CBT for Depressive Symptoms and Binge Drinking Among Young Adults: Two Case Studies 
There are high rates of comorbidity between heavy drinking and depressive symptoms among college students, often resulting in severe alcohol-related consequences. No empirically supported treatment exists that concurrently addresses both of these problems in this population. Research with college students has demonstrated that brief motivational interventions (BMIs) reduce heavy drinking and alcohol-related consequences, and that cognitive behavioral therapy for depression (CBT-D) is effective in reducing depressive symptoms. Thus, a program combining BMI and CBT-D appears ideal for college students with co-occurring binge drinking and depressive symptoms. This manuscript presents the rationale and format of a BMI + CBT-D treatment protocol for this population, and provides a case example of a female college student who received the protocol and experienced improvement in depressive symptoms, a reduction in alcohol use and alcohol-related negative consequences, and an increase in readiness to change alcohol consumption. We discuss theoretical and clinical implications of these findings, and suggest directions for future research.
PMCID: PMC4144760  PMID: 25170188
binge drinking; depressive symptoms; cognitive behavioral therapy treatment; brief motivational interviewing; college students
10.  Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment 
CNS spectrums  2012;17(2):76-86.
To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response.
We screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20–60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined.
Prevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C=41%, C/T=47%, T/T=11%, A/A=66%, A/G=29%, G/G=4%). In the fluoxetine-treated subsample (n=49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response.
The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.
PMCID: PMC4117348  PMID: 22789065
Methylene Tetrahydrofolate Reductase; MTHFR; Methionine Synthase; MS; C677T; A2756G; depression; antidepressant; fluoxetine
11.  The Engagement Interview Protocol (EIP): improving the acceptance of mental health treatment among Chinese immigrants 
Many depressed Chinese immigrants are unfamiliar with Western psychiatric terminology and have high levels of stigma toward psychiatric illnesses, making it difficult to engage them into psychiatric treatment. We have designed the Engagement Interview Protocol (EIP), a semi-standardized protocol that incorporates cultural components to a standard psychiatric evaluation. The EIP elicits patients’ narratives and uses anthropological questions to explore patients’ illness beliefs, which are integrated with patients’ information on medical and psychiatric history, psychosocial background and mental status examination so that treatment options can be negotiated in a culturally sensitive manner. In our field testing on depressed Chinese immigrants, the EIP model was found to be a practical tool that can be completed within the allotted one-hour time frame and was highly effective in facilitating the enrollment of patients in treatment for depression. The EIP is a concise, time-effective, user-friendly protocol that can be used both in research and real-world clinical settings with diverse patient populations.
PMCID: PMC4112467  PMID: 25076983
depression; engagement interview; Chinese Americans; mental disorders
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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