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1.  Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia 
Bipolar Disorders  2009;11(7):701-710.
Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.
We assayed 276 publicly available ‘tag’ single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS).
Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL.
Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.
PMCID: PMC3401899  PMID: 19839995
association; bipolar disorder; circadian; gene; schizoaffective disorder; schizophrenia
2.  Neural substrates of trait ruminations in depression 
Journal of abnormal psychology  2014;123(1):35-48.
Rumination in depression is a risk factor for longer, more intense, and harder-to-treat depressions. But there appear to be multiple types of depressive rumination – whether they all share these vulnerability mechanisms, and thus would benefit from the same types of clinical attention is unclear. In the current study, we examined neural correlates of empirically-derived dimensions of trait rumination in 35 depressed participants. These individuals and 29 never-depressed controls completed 17 self-report measures of rumination and an alternating emotion-processing/executive-control task during functional magnetic resonance imaging (fMRI) assessment. We examined associations of regions of interest—the amygdala and other cortical regions subserving a potential role in deficient cognitive control and elaborative emotion-processing—with trait rumination. Rumination of all types was generally associated with increased sustained amygdala reactivity. When controlling for amygdala reactivity, distinct activity patterns in hippocampus were also associated with specific dimensions of rumination. We discuss the possibly utility of targeting more basic biological substrates of emotional reactivity in depressed patients who frequently ruminate.
PMCID: PMC4128503  PMID: 24661157
rumination; depression; fMRI; emotion; amygdala
3.  The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders 
The American journal of psychiatry  2013;170(11):1249-1262.
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
PMCID: PMC4091043  PMID: 24030475
4.  Preventing Depressive Relapse and Recurrence in Higher Risk Cognitive Therapy Responders: A Randomized Trial of Continuation Phase Cognitive Therapy, Fluoxetine, or Matched Pill Placebo 
JAMA psychiatry  2013;70(11):1152-1160.
Strategies to improve the course of recurrent major depressive disorder (MDD) have great public health relevance. To reduce the risk of relapse/recurrence after acute phase Cognitive Therapy (CT), a continuation phase model of therapy (C-CT) may improve outcomes.
To test the efficacy of C-CT and fluoxetine (FLX) for relapse prevention in a placebo (PBO) controlled randomized trial and compare the durability of prophylaxis after discontinuation of treatments.
A sequential, three stage design with: acute phase (all patients received 12 weeks of CT), 8 month experimental phase (responders at higher risk were randomized to C-CT, FLX, or PBO), and 24 months of longitudinal, post-treatment follow-up.
Two university-based specialty clinics.
523 adults with recurrent MDD began acute phase CT, of which 241 “higher risk” responders were randomized and 181 subsequently entered the follow-up.
CT responders at higher risk for relapse were randomized to receive 8 months of C-CT (n = 86), FLX (n = 86) or PBO (n = 69).
Main Outcome Measures
Survival analyses of relapse/recurrence rates, as determined by “blinded” evaluators using DSM-IV criteria and the LIFE interview.
As predicted, the C-CT or FLX groups were significantly less likely to relapse than the PBO group across 8 months. Relapse/recurrence rates for C-CT and FLX were nearly identical during the 8 months of treatment, although C-CT patients were more likely to accept randomization, stayed in treatment longer, and attended more sessions than those in FLX/PBO. Contrary to prediction, relapse/recurrence rates following the discontinuation of C-CT and FLX did not differ.
Relapse risk was reduced by both C-CT and FLX in an “enriched” randomization sampling only CT responders. The preventive effects of C-CT were not significantly more ‘durable’ than those of FLX after treatment was stopped, suggesting that some higher risk patients may require alternate longer-term interventions.
PMCID: PMC4204630  PMID: 24005123
randomized clinical trial; recurrent depression; cognitive therapy; fluoxetine; placebo; continuation phase; relapse; recurrence
5.  Going Beyond Antidepressant Monotherapy for Incomplete Response in Non-Psychotic Late-Life Depression: A Critical Review 
Many older adults with Major Depressive Disorder (MDD) do not respond to antidepressant monotherapy. While there are evidence-based treatment options to support treatment beyond monotherapy for adults, the evidence for such strategies specifically in late-life MDD is relatively scarce. This review examines the published data describing strategies for antidepressant augmentation or acceleration studied specifically in older adults, including lithium, stimulants, and second-generation antipsychotics. In addition, the authors suggest strategies for future research, such as study of specific agents, refining understanding of the impact of medical or cognitive comorbidity in late-life depression, and comparative effectiveness to examine methods already used in clinical practice.
PMCID: PMC3543487  PMID: 23567381
antidepressant; pharmacotherapy; augmentation; depression
6.  Detecting Critical Decision Points in Psychotherapy and Psychotherapy + Medication for Chronic Depression 
To quantify clinical decision points for identifying depression treatment non-remitters prior to end-of-treatment.
Data come from the psychotherapy arms of a randomized clinical trial for chronic depression. Participants (n=352; 65.6% female; 92.3% White; mean age = 44.3 years) received 12 weeks of Cognitive Behavioral Analysis System of Psychotherapy (CBASP) or CBASP plus an antidepressant medication. In half of the sample, receiver operating curve (ROC) analyses were used to identify efficient percent symptom reduction cut points on the Inventory of Depressive Symptoms-Self Report (IDS-SR) for predicting end-of-treatment nonremission based on the Hamilton Rating Scale for Depression (HRSD). Sensitivity, specificity, predictive values and Cohen’s kappa for identified cut points were calculated using the remaining half of the sample.
Percent IDS-SR symptom reduction at weeks 6 and 8 predicted end of treatment HRSD remission status in both the combined treatment (week 6 cut point = 50.0%, Cohen’s kappa = .42; week 8 cut point = 54.3%, Cohen’s kappa = .45), and psychotherapy only (week 6 cut point = 60.7%, Cohen’s kappa = .41; week 8 cut point = 48.7%, Cohen’s kappa = .49). Week 8 was more reliable for identifying nonremitters in psychotherapy only treatment.
Those with chronic depression who will not remit in structured, time-limited psychotherapy for depression, either alone or in combination with antidepressant medication, are identifiable prior to end-of-treatment. Findings provide an operationalized strategy for designing adaptive psychotherapy interventions.
PMCID: PMC3925064  PMID: 23750462
chronic depression; psychotherapy for depression; psychotherapy nonremission; adaptive designs; receiver operating curve
7.  Efficacy and Safety of Olanzapine/Fluoxetine Combination vs Fluoxetine Monotherapy Following Successful Combination Therapy of Treatment-Resistant Major Depressive Disorder 
Neuropsychopharmacology  2014;39(11):2549-2559.
This study assessed prevention of relapse in patients with treatment-resistant depression (TRD) taking olanzapine/fluoxetine combination (OFC). Patients with major depressive disorder (MDD) who failed to satisfactorily respond to ⩾2 different antidepressants for ⩾6 weeks within the current MDD episode were acutely treated for 6–8 weeks, followed by stabilization (12 weeks) on OFC. Those who remained stable were randomized to OFC or fluoxetine for up to 27 weeks. Time-to-relapse was the primary efficacy outcome defined as 50% increase in Montgomery-Åsberg Depression Rating Scale score with Clinical Global Impressions−Severity of Depression score of ⩾4; hospitalization for depression or suicidality; or discontinuation for lack of efficacy or worsening of depression or suicidality. A total of 444 patients were randomized 1:1 to OFC (N=221) or fluoxetine (N=223). Time-to-relapse was significantly longer in OFC-treated patients compared with fluoxetine-treated patients (p<0.001). Treatment-emergent weight gain and some mean and categorical fasting metabolic changes were significantly greater in OFC-treated patients. Clinically significant weight gain (⩾7%) was observed in 55.7% of patients who remained on OFC throughout the study, including the relapse-prevention phase (up to 47 weeks). There were no significant differences between patients treated with OFC and fluoxetine in extrapyramidal symptoms or serious adverse events. We believe this is the first controlled relapse-prevention study in subjects with TRD that supports continued use of a second-generation antipsychotic beyond stabilization. A thorough assessment of benefits and risks (in particular metabolic changes) associated with continuing treatment with OFC or fluoxetine must be done based on individual patient needs.
PMCID: PMC4207330  PMID: 24801768
8.  Fluoxetine Increases Suicide Ideation Less than Placebo During Treatment of Adults with Minor Depressive Disorder 
Journal of psychiatric research  2013;47(9):1199-1203.
Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with Minor Depressive Disorder.
Research subjects were adult outpatients with Minor Depressive Disorder (N=162), who received fluoxetine or placebo in a prospective, 12-week, double blind randomized trial. The research participants were evaluated weekly with standard rating scales that included 4 suicide-related items; item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 on any of these items.
Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase (p=0.04). Survival analysis revealed that subjects on placebo were significantly more likely (p=0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial.
Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with Minor Depressive Disorder during 12 weeks of treatment.
PMCID: PMC3729337  PMID: 23786912
Minor Depressive Disorder; fluoxetine; antidepressant; treatment emergent suicide ideation
9.  The Relationship Between the Therapeutic Alliance and Treatment Outcome in Two Distinct Psychotherapies for Chronic Depression 
This study tested whether the quality of the patient-rated working alliance, measured early in treatment, predicted subsequent symptom reduction in chronically depressed patients. Secondarily, the study assessed whether the relationship between early alliance and response to treatment differed between patients receiving Cognitive Behavioral Analysis System of Psychotherapy (CBASP) versus Brief Supportive Psychotherapy (BSP).
395 adults (57% female; Mage = 46; 91% Caucasian) who met criteria for chronic depression and did not fully remit during a 12-week algorithm-based, open-label pharmacotherapy trial were randomized to receive either 16–20 sessions of CBASP or BSP in addition to continued, algorithm-based antidepressant medication. Of these, 224 patients completed the Working Alliance Inventory-Short Form at weeks 2 or 4 of treatment. Blind raters assessed depressive symptoms at two-week intervals across treatment using the Hamilton Rating Scale for Depression. Linear mixed models tested the association between early alliance and subsequent symptom ratings while accounting for early symptom change.
A more positive early working alliance was associated with lower subsequent symptom ratings in both the CBASP and BSP, F(1, 1236) =62.48, p<.001. In addition, the interaction between alliance and psychotherapy type was significant, such that alliance quality was more strongly associated with symptom ratings among those in the CBASP treatment group, F(1,1234) = 8.31, p =.004.
The present results support the role of the therapeutic alliance as a predictor of outcome across dissimilar treatments for chronic depression. Contrary to expectations, the therapeutic alliance was more strongly related to outcome in CBASP, the more directive of the two therapies.
PMCID: PMC3742444  PMID: 23339536
alliance; depression; psychotherapy outcome; REVAMP
10.  Nomothetic and Idiographic Symptom Change Trajectories in Acute-Phase Cognitive Therapy for Recurrent Depression 
Journal of consulting and clinical psychology  2013;81(4):10.1037/a0032879.
We tested nomothetic and idiographic convergence and change in three symptom measures during acute-phase cognitive therapy (CT) for depression and compared outcomes among patients showing different change patterns.
Outpatients (N = 362; 69% women; 85% white; age mean = 43 years) with DSM-IV recurrent major depressive disorder completed the Hamilton Rating Scale for Depression (Hamilton, 1960), Beck Depression Inventory (Beck, Ward, Mendelson, Mock, & Erbaugh 1961), and Inventory for Depressive Symptomatology—Self-Report (Rush, Gullion, Basco, Jarrett, & Trivedi, 1996) on 14 occasions, and pre-/post-CT measures of social-interpersonal functioning and negative cognitive content.
The three symptom measures marked the same severity and change constructs, and we offer improved formulas for inter-measure score conversions via their common factor. Pre-post CT symptom reductions were large (ds 1.71-1.92), and nomothetic symptom curves were log-linear (larger improvements earlier and smaller improvements later in CT). Nonetheless, only 30% of individual patients showed clear log-linear changes, whereas other patients showed linear (e.g., steady decreases; 20%), one-step (e.g., a quick drop; 16%), and unclassified (34%) patterns. Log-linear, linear, and one-step patients were generally similar to one another and superior to unclassified patients post-CT in symptom levels, response and stable remission rates, social-interpersonal functioning, and cognitive content (median d = 0.69).
Reaching a low-symptom “destination” at the end of CT via any coherent “path” is more important in the short-term than which path patients take. We discuss implications for theories of change, clinical monitoring of individuals’ progress in CT, and the need to investigate long-term outcomes of patients with differing symptom change patterns.
PMCID: PMC3809821  PMID: 23627652
major depressive disorder; cognitive therapy; symptom assessment; change pattern
11.  Comparison of adjunctive use of aripiprazole with bupropion or selective serotonin reuptake inhibitors/serotonin–norepinephrine reuptake inhibitors: analysis of patients beginning adjunctive treatment in a 52-week, open-label study 
BMC Research Notes  2014;7:459.
This post hoc analysis assessed the safety, tolerability and effectiveness of long-term treatment with aripiprazole adjunctive to either bupropion or selective serotonin reuptake inhibitors (SSRIs)/serotonin–norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD).
Data from de novo patients (did not participate in 2 previous studies) in a 52-week, open-label safety study of adjunctive aripiprazole after documented inadequate response to 1–4 antidepressant treatments (ADTs; SSRI, SNRI, or bupropion) were analyzed post hoc. Assessments included safety and tolerability, sexual functioning (Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI]) and Clinical Global Impressions–Severity (CGI-S).
Forty-seven patients received bupropion plus aripiprazole and 245 received an SSRI/SNRI plus aripiprazole; 19 (40.4%) and 78 (31.8%), respectively, completed 52 weeks of treatment, and 46 and 242, respectively, received ≥1 dose of study medication (safety sample). Median time to discontinuation (any reason) was 184.0 days. Overall, 97.8% of patients in the bupropion group and 93.8% in the SSRI/SNRI group experienced ≥1 adverse event. The most common treatment-emergent adverse events were fatigue (26.1%) and somnolence (21.7%) with bupropion and fatigue (23.6%) and akathisia (23.6%) with an SSRI/SNRI. Mean change in body weight at week 52 (observed cases) was +3.1 kg for bupropion and +2.4 kg for an SSRI/SNRI. Treatment-emergent, potentially clinically relevant abnormalities in fasting glucose occurred in 8.3% of patients with bupropion and 17.4% with an SSRI/SNRI; for abnormalities in fasting total cholesterol, the incidence was 25.0% and 34.7%, respectively. Mean (SE) change from baseline in fasting glucose was 1.4 (1.9) mg/dL with bupropion and 2.7 (1.5) mg/dL with an SSRI/SNRI. Baseline MGH-SFI item scores indicated less severe impairment with bupropion versus an SSRI/SNRI; in both groups most MGH-SFI items exhibited improvement at week 52. Mean CGI-S improvement at week 52 (last observation carried forward) was -1.4 with bupropion and -1.5 with an SSRI/SNRI (efficacy sample).
There were no unexpected AEs with long-term adjunctive aripiprazole therapy when added to either bupropion or SSRIs/SNRIs, and symptom improvement was similar between ADT groups. Sexual functioning in patients with MDD on antidepressants was also modestly improved after adding aripiprazole.
Trial registration NCT00095745 (November 9, 2004).
PMCID: PMC4119176  PMID: 25037144
Adjunctive antidepressant; Atypical antipsychotic; Aripiprazole; Bupropion; Dopamine; Major depressive disorder; Selective serotonin reuptake inhibitors; Serotonin–norepinephrine reuptake inhibitors; Sexual dysfunction
12.  Linkage Disequilibrium Mapping of the Chromosome 6q21–22.31 Bipolar I Disorder Susceptibility Locus 
We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case–control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P=6.72× 10−5) was observed in the case–control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.
PMCID: PMC4067321  PMID: 19308960
bipolar disorder; genetic; association; SLC22A16; 6q
13.  Acute Phase Cognitive Therapy for Recurrent Major Depressive Disorder: Who Drops Out and How Much do Patient Skills Influence Response? 
Behaviour research and therapy  2013;51(0):221-230.
The aims were to predict cognitive therapy (CT) noncompletion and to determine, relative to other putative predictors, the extent to which the patient skills in CT for recurrent major depressive disorder predicted response in a large, two-site trial.
Among 523 outpatients aged 18-70, exposed to 12-14 weeks of CT, 21.6% dropped out. Of the 410 completers, 26.1% did not respond. To predict these outcomes, we conducted logistic regression analyses of demographics, pre-treatment illness characteristics and psychosocial measures, and mid-treatment therapeutic alliance.
The 17-item Hamilton Rating Scale for Depression (HRSD17) scores at entry predicted drop-out and nonresponse. Patients working for pay, of non-Hispanic white race, who were older, or had more education were significantly more likely to complete. Controlling for HRSD17, significant predictors of nonresponse included: lower scores on the Skills of Cognitive Therapy-Observer Version (SoCT-O), not working for pay, history of only two depressive episodes, greater pre-treatment social impairment. Mid-phase symptom reduction was a strong predictor of final outcome.
These prognostic indicators forecast which patients tend to be optimal candidates for standard CT, as well as which patients may benefit from changes in therapy, its focus, or from alternate modalities of treatment. Pending replication, the findings underscore the importance of promoting patients’ understanding and use of CT skills, as well as reducing depressive symptoms early. Future research may determine the extent to which these findings generalize to other therapies, providers who vary in competency, and patients with other depressive subtypes or disorders.
PMCID: PMC3685278  PMID: 23485420
depression; cognitive therapy; predictors; patient skills; response patterns; attrition
14.  Replication and Extension: Separate Personality Traits from States to Predict Depression 
Journal of personality disorders  2013;28(2):225-246.
Changes in personality trait levels often parallel episodes of major depressive disorder (MDD), whereas trait factor structures and substantial retest correlations are preserved. We explicated this dual state/trait nature of personality assessments among adults with recurrent MDD (N=351) receiving cognitive therapy (CT). We tested stability and change in the Schedule for Nonadaptive and Adaptive Personality, 2nd Edition (SNAP-2; Clark et al., in press), separated state and trait variance, and predicted depressive symptoms and clinical outcomes. Many SNAP scale scores changed in CT (e.g., positive temperament increased, negative temperament decreased), and decreases in depressive symptoms accounted for most scales' score changes. Nonetheless, SNAP scales' state and trait components predicted depressive symptoms early and late in CT as well as clinical outcomes, and state components predicted changes in symptoms and clinical outcomes. These results support the validity of the SNAP-2 among depressed patients and highlight the salience of personality-relevant state affect.
PMCID: PMC3855180  PMID: 23786268
depression; cognitive therapy; state; trait; Schedule for Nonadaptive and Adaptive Personality (SNAP)
15.  Remission Prognosis for Cognitive Therapy for Recurrent Depression Using the Pupil: Utility and Neural Correlates 
Biological psychiatry  2011;69(8):726-733.
Although up to 60% of people with major depressive disorder (MDD) respond to Cognitive Therapy (CT) in controlled trials, clinicians do not routinely use standardized assessments to inform which patients should receive this treatment. Inexpensive non-invasive prognostic indicators could aid in matching patients with appropriate treatments. Pupillary response to emotional information is an excellent candidate, reflecting limbic reactivity and executive control. This study examined 1) whether pre-treatment assessment of pupillary responses to negative information were associated with remission in CT, and 2) their associated brain mechanisms.
We examined whether pre-treatment pupillary responses to emotional stimuli were prognostic for remission in an inception cohort of 32 unipolar depressed adults to 16–20 sessions of CT. Twenty patients were then assessed on the same task using fMRI. Pupillary responses were assessed in 51 never-depressed controls for reference.
Remission was associated with either low initial severity or the combination of higher initial severity and low sustained pupil dilation responses to negative words (87% correct classification of remitters and non-remitters (93% sensitivity, 80% specificity); 88% correct classification of high-severity participants, p<.01, 90% sensitivity, 92% specificity). Increased pupillary responses were associated with increased activity in dorso-lateral prefrontal regions associated with executive control and emotion regulation.
For patients with higher severity, disruptions of executive control mechanisms responsible for initiating emotion regulation, which are indexed by low sustained pupil responses and targeted in therapy, may be key to remitting in this intervention. These mechanisms can be measured using inexpensive noninvasive psychophysiological assessments.
PMCID: PMC3951934  PMID: 21447417
Cognitive Therapy; Remission; Psychotherapy; Depression; Pupilometry; Emotion; Affect; Psychophysiology
16.  Sustained gamma-band EEG following negative words in depression and schizophrenia 
Sustained and elaborative emotional information processing in depression and decreased affective elaboration in schizophrenia are considered hallmarks of these disorders but have not been directly measured. Gamma-band (35–45 Hz) EEG, has been associated with semantic functions such as feature binding and may index these elaborative processing. This study examined whether there were group differences in baseline and sustained gamma-band EEG following emotional stimuli in healthy adults as well as adults with depression and schizophrenia.
24 never-depressed healthy controls, 14 patients with DSM-IV unipolar major depressive disorder, and 15 patients with DSM-IV schizophrenia completed a lexical emotion identification task during EEG assessment. Gamma band EEG (35–45 Hz) in response to negative words was the primary dependent measure.
As predicted, depressed individuals displayed sustained and increased gamma-band EEG throughout the task, and particularly in the seconds following negative words. Individuals with schizophrenia displayed decreased gamma-band activity throughout the task.
These data suggest that gamma-band EEG, measured over several seconds, may serve as a useful index of sustained semantic information processing. Depressed individuals appear to engage in sustained elaboration following emotional stimuli, whereas individuals with schizophrenia are not as prone to this type of elaborative processing.
PMCID: PMC3951951  PMID: 20005267
17.  Towards clinically useful neuroimaging in depression treatment: Is subgenual cingulate activity robustly prognostic for depression outcome in Cognitive Therapy across studies, scanners, and patient characteristics? 
Archives of general psychiatry  2012;69(9):913-924.
40–60% of unmedicated depressed individuals respond to Cognitive Therapy (CT) in controlled trials. Multiple previous studies suggest that activity in the subgenual anterior cingulate predicts outcome in CT for depression, but there have been no prospective replications.
This study prospectively examined whether subgenual cingulate activity is a reliable and robust prognostic outcome marker for CT for depression and whether its activity changes in treatment.
Two inception cohorts were assessed with fMRI on different scanners on a task sensitive to sustained emotional information processing before and after 16–20 sessions of CT, along with a sample of control participants tested at comparable intervals.
Therapy took place in a hospital outpatient clinic.
Participants included 49 unmedicated depressed adults and 35 healthy control participants.
Main Outcome Measures
Pre-treatment subgenual anterior cingulate activity in an a priori region in response to negative words was correlated with residual severity and used to classify response and remission.
As expected, in both samples, participants with the lowest pre-treatment sustained subgenual cingulate (sgACC; BA25) reactivity in response to negative words displayed the most improvement in CT (R2=.29, >75% correct classification of response, >70% correct classification of remission). Other a priori regions explained additional variance. Response/Remission in Cohort 2 was predicted based on thresholds from Cohort 1. sgACC activity remained low for remitters following treatment.
Neuroimaging provides a quick, valid, and clinically applicable way of assessing neural systems associated with treatment response/remission. sgACC activity, in particular, may reflect processes which interfere with treatment, e.g,. emotion generation in addition to its putative regulatory role; alternately, its absence may facilitate treatment response.
PMCID: PMC3951953  PMID: 22945620
Cognitive Therapy; Mood Disorders – Unipolar; Brain Imaging Techniques; Cognitive Neuroscience; Emotion
18.  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
20.  Dysfunctional Attitudes as a Moderator of Pharmacotherapy and Psychotherapy for Chronic Depression 
Journal of psychiatric research  2012;47(1):113-121.
Individuals with chronic depression exhibit heterogeneous responses to treatment. Important individual differences may therefore exist within this particularly difficult to treat population that act as moderators of treatment response.
The present study examined whether pretreatment levels of dysfunctional attitudes (DA) moderated treatment response in a large sample of chronically depressed individuals. Data were taken from the Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP) treatment study – a multi-site treatment and augmentation study of 808 chronically depressed individuals. REVAMP comprised two phases: 1) a 12-week open-label antidepressant trial and 2), a subsequent phase, in which phase 1 non-remitters (N=491) were randomized to either receive an ongoing medication algorithm alone, medication plus cognitive behavioral analysis system of psychotherapy, or medication plus brief supportive psychotherapy.
In phase 1, compared to the pharmacotherapy response of patients with lower DA scores, the response for patients with higher DA scores was steeper, but leveled off towards the end of the phase. In phase 2, DA predicted a differential response in the medication only arm, but not in the two psychotherapy+medication conditions. Specifically, in the phase 2 medication only condition, patients with higher DA improved while those with lower DA scores did not.
These results indicate that the relation between DA and treatment response in chronic depression is complex, but suggest that greater DA may be associated with a steeper reduction and/or better response to pharmacotherapy.
PMCID: PMC3501539  PMID: 23102821
dysfunctional attitudes; predictor; treatment; response; chronic depression
21.  Impact of Reproductive Status and Age on Response of Depressed Women to Cognitive Therapy 
Journal of Women's Health  2013;22(1):58-66.
Previous research suggests that reproductive hormones are potential affective modulators in mood disorders and may influence response to antidepressant medications. To our knowledge, there are no data on relationships between hormonal status and response to psychotherapy for recurrent major depressive disorder (MDD).
At two sites, female outpatients (n=353), aged 18–70, with recurrent MDD received 12–14 weeks of cognitive therapy (CT). Menopausal status and age were based on self-report. In the parent study, nonresponse to therapy was defined as persistence of a major depressive episode (MDE) as defined by the DSM-IV or a final Hamilton Rating Scale for Depression-17-Item (HRSD17) score of ≥ 12 or both. More traditional definitions of response (at least a 50% reduction in pretreatment HRSD17) and remission (a final HRSD17 ≤ 6) were also examined.
Controlling for pretreatment HRSD17 scores, there were no significant differences found in the rates of response to CT or symptom status among premenopausal, perimenopausal, and postmenopausal women.
We found no support for the hypotheses that response to CT or the rates of change in depressive symptoms are moderated by reproductive status. The findings, however, are limited by the absence of early follicular phase serum sampling/analysis to estimate hormone levels and the reliance on self-report to establish menopausal status. These data motivate a full investigation of the effects of reproductive status on response to psychosocial interventions.
PMCID: PMC3546363  PMID: 23305218
22.  General Medical Burden in Bipolar Disorder: Findings from the LiTMUS Comparative Effectiveness Trial 
Acta psychiatrica Scandinavica  2013;129(1):10.1111/acps.12101.
This study examined general medical illnesses and their association with clinical features of bipolar disorder.
Data were cross-sectional and derived from the Lithium Treatment – Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n=264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥ 4 and < 4, respectively.
The baseline prevalence of significant medical comorbidity was 53% (n=139). Patients with high medical burden were more likely to present in a major depressive episode (P=.04), meet criteria for obsessive-compulsive disorder (P=.02), and experience a greater number of lifetime mood episodes (P=0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P=.002). Sixty-nine percent of the sample was overweight or obese as defined by body mass index (BMI), with African-Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥ 35; 31%, n=14).
The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns. (Funded by NIMH Contract N01MH80001; number NCT00667745).
PMCID: PMC3789858  PMID: 23465084
Bipolar disorder; medical comorbidity; obesity; lithium; effectiveness
23.  A Review of Vilazodone, Serotonin, and Major Depressive Disorder 
Objective: To review the mechanism of selective serotonin reuptake inhibitor (SSRI)–mediated serotonergic neurotransmission, focusing on serotonin 1A (5-HT1A) autoreceptors, which are proposed to be involved in delaying therapeutic efficacy. Vilazodone was specifically designed to function both as an SSRI and a partial agonist at 5-HT1A receptors. This combined mechanism is proposed to decrease time to efficacy, minimize sexual side effects, and provide concomitant anxiolytic properties.
Data Sources: A PubMed search of all English-language articles from January 1990 to January 2013 was conducted using the search terms depression and 5-HT1A, depression and buspirone, depression and pindolol, and vilazodone.
Study Selection: We found 47 articles and abstracts that were selected for inclusion on the basis of information about the pharmacology of 5-HT1A receptors and the clinical data on pindolol, buspirone, and vilazodone in depression.
Data Extraction: This review summarizes current literature involving antidepressant activity, the role of 5-HT1A autoreceptors, and clinical trials involving serotonin reuptake inhibition in conjunction with 5-HT1A agonists and partial agonists, with a focus on vilazodone.
Results:Vilazodone has demonstrated efficacy in 2 large, randomized, double-blind, placebo-controlled trials in major depressive disorder. Results suggest that vilazodone has a low incidence of sexual side effects and is effective in patients with high levels of anxiety. A pooled analysis shows evidence of significant symptom reduction after only 1 week of therapy.
Conclusions: If future studies corroborate the clinical benefits attributed to its mechanism of action, vilazodone may show potential advantages in terms of onset of action, sexual side effects, and anxiolytic activity in patients with major depressive disorder.
PMCID: PMC4048143  PMID: 24940527
24.  Comparative Efficacy and Durability of Continuation Phase Cognitive Therapy for Preventing Recurrent Depression: Design of a Double-Blinded, Fluoxetine- and Pill-Placebo–Controlled, Randomized Trial with 2-Year Follow-up 
Contemporary clinical trials  2010;31(4):355-377.
Major depressive disorder (MDD) is highly prevalent and associated with disability and chronicity. Although cognitive therapy (CT) is an effective short-term treatment for MDD, a significant proportion of responders subsequently suffer relapses or recurrences.
This design prospectively evaluates: 1) a method to discriminate CT-treated responders at lower versus higher risk for relapse; and 2) the subsequent durability of 8-month continuation phase therapies in randomized higher risk responders followed for an additional 24-months. The primary prediction is: after protocol treatments are stopped, higher risk patients randomly assigned to continuation phase CT (C-CT) will have a lower risk of relapse/recurrence than those randomized to fluoxetine (FLX).
Outpatients, aged 18 to 70 years, with recurrent MDD received 12–14 weeks of CT provided by 15 experienced therapists from two sites. Responders (i.e., no MDD and 17-item Hamilton Rating Scale for Depression ≤ 12) were stratified into higher and lower risk groups based on stability of remission during the last 6 weeks of CT. The lower risk group entered follow-up for 32 months; the higher risk group was randomized to 8 months of continuation phase therapy with either C-CT or clinical management plus either double-blinded FLX or pill placebo. Following the continuation phase, higher risk patients were followed by blinded evaluators for 24 months.
The trial began in 2000. Enrollment is complete (N=523). The follow-up continues.
The trial evaluates the preventive effects and durability of acute and continuation phase treatments in the largest known sample of CT responders collected worldwide.
PMCID: PMC2936266  PMID: 20451668
relapse prevention; recurrent depression; cognitive therapy; fluoxetine; longitudinal follow-up
25.  Association Between Therapeutic Alliance, Care Satisfaction, and Pharmacological Adherence in Bipolar Disorder 
Journal of clinical psychopharmacology  2013;33(3):10.1097/JCP.0b013e3182900c6f.
We sought to understand the association of specific aspects of care satisfaction, such as patients’ perceived relationship with their psychiatrist and access to their psychiatrist and staff, and therapeutic alliance with participants’ likelihood to adhere to their medication regimens among patients with bipolar disorder.
We examined data from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder, an effectiveness study investigating the course and treatment of bipolar disorder. We expected that participants (n = 3037) with positive perceptions of their relationship with their psychiatrist and quality of psychopharmacologic care, as assessed by the Helping Alliance Questionnaire and Care Satisfaction Questionnaire, would be associated with better medication adherence. We utilized logistic regression models controlling for already established factors associated with poor adherence.
Patients’ perceptions of collaboration, empathy, and accessibility were significantly associated with adherence to treatment in individuals with bipolar disorder completing at least 1 assessment. Patients’ perceptions of their psychiatrists’ experience, as well as of their degree of discussing medication risks and benefits, were not associated with medication adherence.
Patients’ perceived therapeutic alliance and treatment environment impact their adherence to pharmacotherapy recommendations. This study may enable psychopharmacologists’ practices to be structured to maximize features associated with greater medication adherence.
PMCID: PMC3873324  PMID: 23609394
therapeutic alliance; clinical practice; medication adherence; bipolar disorder; treatment

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