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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.  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
3.  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
4.  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)
5.  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
6.  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
7.  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
8.  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
10.  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
11.  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
12.  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
13.  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
14.  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
Cognitive therapy and research  2008;32(4):10.1007/s10608-008-9191-0.
Trait rumination, a tendency to focus on depressive symptoms and negative information, is associated with longer and more severe episodes of depression. This study examined whether trait rumination was also associated with initial remission from unipolar depression in Cognitive Therapy, which we hypothesized would target this coping style. Eighty one patients completed measures of depressive severity and rumination before and after 16–20 sessions of procedurally determined Cognitive Therapy. Pre-treatment rumination and severity were generally associated with later initial remission and lower odds of achieving remission. Limited evidence also suggested that for the most severe patients, rumination was associated with earlier initial remission and greater odds of achieving initial remission. Cognitive Therapy was associated with significant reductions in both rumination and severity. Results suggest that 1) pre-treatment assessment of rumination and severity could help to plan treatment course and 2) Cognitive Therapy is associated with changes in cognitive coping styles.
PMCID: PMC3864875  PMID: 24353355
Cognitive Therapy; Rumination; Response Styles Theory; Depression
16.  A Meta-analysis of Factors Impacting Detection of Antidepressant Efficacy in Clinical Trials: The Importance of Academic Sites 
Neuropsychopharmacology  2012;37(13):2830-2836.
Variability in placebo response greatly complicates the design, conduct, and interpretation of clinical trials of antidepressant medications. To identify factors that impact detection of antidepressant–placebo differences, we conducted a meta-analysis of all relevant phase II–IV clinical trials for major depressive disorder conducted by the manufacturer of venlafaxine and desvenlafaxine completed by March 2011. We examined 15 factors potentially relevant to trial outcomes, using the standardized mean difference on the Hamilton Rating Scale for Depression (HAM-D17) score as the primary outcome. Thirty trials comprising 8933 patients were included. In univariate analyses, antidepressant efficacy (ie, drug vs placebo difference) was predicted most strongly (β=3.74, p=0.0002) by the proportion of patients in the trial enrolled from academic sites. Other factors predicting larger drug–placebo differences included lower participant completion rate, fewer post-baseline study visits, earlier year of study, and study drug (venlafaxine>desvenlafaxine). In multivariate meta-regression modeling, only the proportion of patients from academic sites maintained statistical significance as a predictor of drug–placebo separation for both HAM-D17 continuous score change (β=2.24, p=0.034) and response rate (β=2.26, p=0.035). Including a higher proportion of academic sites may increase the ability to detect differences between active drug and placebo in clinical trials of major depressive disorder.
PMCID: PMC3499718  PMID: 22910458
Academic Medical Centers; Antidepressive Agents; Clinical Pharmacology/Clinical Trials; Depression; Unipolar/Bipolar; Drug Discovery/Development; Ethics; Mood/Anxiety/Stress Disorders; Placebo; Signal Detection; Venlafaxine; placebo; academic medical centers; signal detection; antidepressants; venlafaxine; desvenlafaxine
17.  Change in Psychosocial Functioning and Depressive Symptoms during Acute-Phase Cognitive Therapy for Depression 
Psychological medicine  2011;42(2):317-326.
Major Depressive Disorder (MDD) is highly prevalent, is recurrent, and impairs people’s work, relationships, and leisure. Acute-phase treatments improve psychosocial impairment associated with MDD, but how these improvements occur is unclear. In this study, we tested the hypotheses that reductions in depressive symptoms exceed, precede, and predict improvements in psychosocial functioning.
Patients with recurrent MDD (N = 523; 68% women, 81% Caucasian; M = 42 years old) received acute-phase Cognitive Therapy (CT; Beck, Rush, Shaw & Emery, 1979). We measured functioning and symptom severity with the Social Adjustment Scale—Self-Report (Weissman & Bothwell, 1976), Range of Impaired Functioning Tool (Leon et al., 1999), Beck Depression Inventory (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961), Hamilton Rating Scale for Depression (Hamilton, 1960) and Inventory for Depressive Symptomatology—Self-Report (Rush et al., 1996). We tested cross-lagged correlations between functioning and symptoms measured at baseline and the beginning, middle and end of acute phase CT.
Pre- to post- treatment improvement in psychosocial functioning and depressive symptoms was large and inter-correlated. Depressive symptoms improved more and sooner than did psychosocial functioning. But among four assessments across the course of treatment, improvements in functioning more strongly predicted later improvement in symptoms than vice versa.
Improvements in psychosocial functioning and depressive symptoms correlate substantially during acute-phase CT, and improvements in functioning may play a role in subsequent symptom reduction during acute-phase CT.
PMCID: PMC3830677  PMID: 21781377
18.  Assessing Rates and Predictors of Tachyphylaxis During the Prevention of Recurrent Episodes of Depression With Venlafaxine ER for Two Years (PREVENT) Study 
Psychopharmacology bulletin  2009;42(3):5-20.
Antidepressant tachyphylaxis describes the return of apathetic depressive symptoms, such as fatigue and decreased motivation, despite continued use of a previously effective treatment.
Data were collected from a multiphase, double-blind, placebo-controlled study that assessed the efficacy of venlafaxine extended release (ER) during 2 sequential 1-year maintenance phases (A and B) in patients with recurrent major depressive disorder (MDD). The primary outcome was the cumulative probability of tachyphylaxis in patients receiving venlafaxine ER, fluoxetine, or placebo. Tachyphylaxis was defined as Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) scored ≥ 7 in patients with prior satisfactory therapeutic response. A Kaplan-Meier estimate of the cumulative probability of not experiencing tachyphylaxis, and a 2-sided Fisher exact test was used to assess the relationship between tachyphylaxis and recurrence.
The maintenance phase A population was comprised of 337 patients (venlafaxine ER [n = 129], fluoxetine [n = 79], placebo [n = 129]), whereas 128 patients (venlafaxine ER [n = 43], fluoxetine [n = 45], placebo [n = 40]) were treated during maintenance phase B. No difference in the probability of experiencing tachyphylaxis were observed between the active treatment groups during either maintenance phase; however, a significant difference between venlafaxine ER and placebo was observed at the completion of maintenance phase A. A significant relationship between tachyphylaxis and recurrence was observed.
Despite demonstrating psychometric validity and reliability, the current definition of tachyphylaxis has not been widely studied
Although no significant differences were observed in the probability of tachyphylaxis among patients receiving active treatment, the relationship between tachyphylaxis and recurrence suggests that tachyphylaxis may be a predrome of recurrence.
PMCID: PMC3806307  PMID: 19752838
loss of antidepressant response; psychopharmacology; major depressive disorder; serotonin norepinephrine reuptake inhibitor; Rothschild Scale for Antidepressant Tachyphylaxis
19.  Patient Treatment Preference As a Predictor of Response and Attrition in Treatment for Chronic Depression 
Depression and anxiety  2012;29(10):896-905.
Findings regarding the relationship between patient treatment preference and treatment outcome are mixed. This is a secondary data analysis investigating the relationship between treatment preference, and symptom outcome and attrition in a large 2-phase depression treatment trial.
Patients met DSM-IV criteria for chronic forms of depression. Phase I was a 12-week, nonrandomized, open-label trial in which all participants (n=785) received antidepressant medication(s) (ADM). Phase I nonremitters were randomized to Phase II, in which they received 12 weeks of either Cognitive-Behavioral System of Psychotherapy (CBASP) + ADM (n=193), Brief Supportive Psychotherapy (BSP) + ADM (n=187), or ADM only (n=93). Participants indicated their treatment preference (medication only, combined treatment or no preference) at study entry. Symptoms were measured at 2-week intervals with the 24-item Hamilton Rating Scale for Depression (HAM-D).
A large majority of patients reported a preference for combined treatment. Patients who preferred medication only were more likely to endorse a chemical imbalance explanation for depression, whereas those desiring combined treatment were more likely to attribute their depression to stressful experiences. In Phase I, patients who expressed no treatment preference showed greater rates of HAM-D symptom reduction than those with any preference, and patients with a preference for medication showed higher attrition than those preferring combined treatment. In Phase II, baseline treatment preference was not associated with symptom reduction or attrition.
Treatment preferences may moderate treatment response and attrition in unexpected ways. Research identifying factors associated with differing preferences may enable improved treatment retention and response.
PMCID: PMC3463778  PMID: 22767424
treatment outcome; treatment engagement
20.  “Barriers to Cognitive Behavioral Therapy Homework Completion Scale- Depression Version”: Development and Psychometric Evaluation 
We conducted a two-phase study to develop and evaluate the psychometric properties of an instrument to identify barriers to Cognitive Behavioral Therapy (CBT) homework completion in a depressed sample. In Phase I, we developed an item pool by interviewing 20 depressed patients and 20 CBT therapists. In Phase II, we created and administered a draft instrument to 56 people with depression. Exploratory Factor Analysis revealed a 2-factor oblique solution of “Patient Factors” and “Therapy/Task Factors.” Internal consistency coefficients ranged from .80 to .95. Temporal stability was demonstrated through Pearson correlations of .72 (for the therapist/task subscale) to .95 (for the patient subscale) over periods of time that ranged from 2 days to 3 weeks. The patient subscale was able to satisfactorily classify patients (75 to 79 %) with low and high adherence at both sessions. Specificity was .66 at both time points. Sensitivity was .80 at sessions B and .77 at session C. There were no consistent predictors of assignment compliance when measured by the Assignment Compliance Rating Scale (Primakoff, Epstein, & Covi, 1986). The Rating Scale and subscale scores did, however, correlate significantly with assignment non-compliance (.32 to .46).
PMCID: PMC3774296  PMID: 24049556
Cognitive Behavioral Therapy; Homework; Adherence; Compliance; reliability; validity
21.  Psychosocial outcomes in patients with recurrent major depressive disorder during 2 years of maintenance treatment with venlafaxine extended release 
Journal of affective disorders  2010;126(3):420-429.
Psychosocial outcomes from the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years (PREVENT) study were evaluated.
Adult outpatients with recurrent major depressive disorder (MDD) and response or remission following 6-month continuation treatment with venlafaxine extended release (ER) were randomized to receive venlafaxine ER or placebo for 1 year. Patients without recurrence on venlafaxine ER during year 1 were randomized to venlafaxine ER or placebo for year 2. Psychosocial functioning was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire—Short Form (Q-LES-Q), Life EnjoymentScale—Short Version (LES-S), Social Adjustment Scale—Self-Report (SAS-SR) total and individual factors, Short Form Health Survey (SF-36) (vitality, social functioning, and role function-emotional items), and Longitudinal Interval Follow-up Evaluation (LIFE).
At year 1 end, better overall psychosocial functioning was seen among patients randomly assigned to venlafaxine ER (n=129) vs placebo (n=129), with significant differences at end point on SF-36 role function-emotional, Q-LES-Q, and SAS-SR total, and work, house work, social/leisure, and extended-family factor scores (p≤0.05). At year 2 end, significant differences favored venlafaxine ER (n=43) vs placebo (n=40)on SF-36 vitality and rolefunction-emotional, Q-LES-Q, LES-S, LIFE, and SAS-SR total, social/leisure, and extended-family factor scores (p≤0.05).
Patients with chronic MDD or treatment resistance were excluded and long-term specialist care was a financial incentive for treatment compliance. Discontinuation-related adverse events may have compromised the integrity of the treatment blind.
For patients with recurrent MDD, 2 years’ maintenance therapy with venlafaxine ER may improve psychosocial functioning vs placebo.
PMCID: PMC3705737  PMID: 20510459
Venlafaxine extended release; Psychosocial outcomes; Major depressive disorder; Maintenance treatment
22.  Methods to Limit Attrition in Longitudinal Comparative Effectiveness Trials: Lessons from the Lithium Use for Bipolar Disorder (LiTMUS) Study 
High attrition rates which occur frequently in longitudinal clinical trials of interventions for bipolar disorder limit the interpretation of results.
The aim of this article is to present design approaches that limited attrition in the Lithium Use for Bipolar Disorder (LiTMUS) Study.
LiTMUS was a 6-month randomized, longitudinal multi-site comparative effectiveness trial that examined bipolar participants who were at least mildly ill. Participants were randomized to either low to moderate doses of lithium or no lithium, in addition to other treatments needed for mood stabilization administered in a guideline-informed, empirically supported, and personalized fashion (N=283).
Components of the study design that may have contributed to the low attrition rate of the study included use of: (1) an intent-to-treat design; (2) a randomized adjunctive single-blind design; (3) participant reimbursement; (4) intent-to-attend the next study visit (includes a discussion of attendance obstacles when intention is low); (5) quality care with limited participant burden; and (6) target windows for study visits.
Site differences and the effectiveness and tolerability data have not been analyzed yet.
These components of the LiTMUS study design may have reduced the probability of attrition which would inform the design of future randomized clinical effectiveness trials.
PMCID: PMC3700408  PMID: 22076437
Attrition; Randomized Clinical Trial Design; Bipolar disorder; Lithium
23.  Faster Remission of Chronic Depression With Combined Psychotherapy and Medication Than With Each Therapy Alone 
The main aim of the present novel reanalysis of archival data was to compare the time to remission during 12 weeks of treatment of chronic depression following antidepressant medication (n = 218), psychotherapy (n = 216), and their combination (n = 222). Cox regression survival analyses revealed that the combination of medication and psychotherapy produced full remission from chronic depression more rapidly than either of the single modality treatments, which did not differ from each other. Receiver operating characteristic curve analysis was used to explore predictors (treatment group, demographic, clinical, and psychosocial) of remission. For those receiving the combination treatment, the most likely to succeed were those with low baseline depression (24-item Hamilton Rating Scale for Depression [HRSD; M. Hamilton, 1967] score < 26) and those with high depression scores but low anxiety (HRSD ≥ 26 and Hamilton Anxiety Rating Scale [M. Hamilton, 1959] <14). Both profiles were associated with at least 40% chance of attaining full remission. The model did not identify predictors for those receiving medication or psychotherapy alone, and it did not distinguish between the 2 monotherapies. The authors conclude that combined antidepressant medications and psychotherapy result in faster full remission of chronic forms of major depressive disorder.
PMCID: PMC3694578  PMID: 18540739
chronic depression; remission; psychotherapy; antidepressant medications; combined treatments
24.  Interpersonal problems as predictors of therapeutic alliance and symptom improvement in cognitive therapy for depression 
Journal of Affective Disorders  2012;138(3):458-467.
The degree to which interpersonal problems of depressed patients improve over the course of cognitive therapy (CT) and relate to the quality of the therapeutic alliance and to symptom improvement, remain unclear.
We analyzed data of adult outpatients (N = 523) with major depressive disorder participating in a clinical trial to determine the factor structure of the Inventory of Interpersonal Problems-Circumplex (IIP-C) and to relate the observed factor scores to the quality of the therapeutic alliance and symptom improvement over the course of CT. Patients received 16–20 sessions protocol (50–60 minutes each) of individual CT according to the treatment manual by Beck et al. (1979).
We found a three-factor structure (interpersonal distress, agency, and communion) of interpersonal problems. Interpersonal distress decreased (d = .90), but interpersonal style did not change substantively during CT (communion d = .03; agency d = .14). High initial agency scores related negatively to the therapeutic alliance (β = −.12), whereas high initial communion scores related positively to the therapeutic alliance (β = .15). Elevated pre-treatment interpersonal distress scores were related to both weaker therapeutic alliances (β = .13) and higher symptom levels throughout treatment (β = .10).
All patients in this study had recurrent MDD and it is therefore uncertain whether the results would generalize to patients with other psychiatric disorders.
This study supports the use of the IIP-C as a comprehensive measure of patients' interpersonal style and interpersonal distress. The IIP-C measured before CT showed some predictive validity with respect to therapeutic alliance measured at the midpoint and therapy outcome. The clinical importance of these findings is discussed.
PMCID: PMC3306447  PMID: 22306232
Recurrent Depression; Cognitive Therapy; Personality; Interpersonal Style; Therapeutic Alliance
25.  Cognitive Reactivity, Dysfunctional Attitudes, and Depressive Relapse and Recurrence in Cognitive Therapy Responders 
Behaviour Research and Therapy  2012;50(5):280-286.
Dysfunctional attitudes can foreshadow depressive relapse/recurrence. Priming mood, through induction paradigms, is hypothesized to activate dysfunctional attitudes. Cognitive reactivity (CR) refers to mood-linked increases in dysfunctional attitudes after priming. Here we explored the extent to which CR as well as residual, unprimed, dysfunctional attitudes predicted depressive relapse/recurrence among depressed patients who responded to acute phase cognitive therapy (CT). Consenting adults, aged 18–70, with recurrent major depressive disorder (n = 523) participated in a two-site randomized controlled trial examining the durability of continuation phase treatments. Patients received 16–20 sessions of CT. Among the 245 incompletely remitted responders, 213 agreed to undergo a mood induction paradigm. After 8 months of continuation phase treatments, participants were followed an additional 24 months. Although the mood induction significantly lowered mood in 80% of responders, the expected CR was not evident. By contrast, higher unprimed dysfunctional attitudes following CT did predict relapse/recurrence over 20 and 32 months post randomization. The findings of this large longitudinal study of incompletely remitted CT responders challenge the notion that it is necessary to prime mood in order to maximize dysfunctional attitudes’ prediction of relapse and/or recurrence. While findings cannot be generalized beyond CT responders, they emphasize the clinical importance of reducing dysfunctional attitudes in preventing depression.
PMCID: PMC3336865  PMID: 22445946
depression; cognitive therapy; cognitive reactivity; mood induction; dysfunctional attitudes

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