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.
association; bipolar disorder; circadian; gene; schizoaffective disorder; schizophrenia
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.
Cognitive Therapy; Rumination; Response Styles Theory; Depression
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.
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
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.
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.
treatment outcome; treatment engagement
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).
Cognitive Behavioral Therapy; Homework; Adherence; Compliance; reliability; validity
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.
Venlafaxine extended release; Psychosocial outcomes; Major depressive disorder; Maintenance treatment
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.
Attrition; Randomized Clinical Trial Design; Bipolar disorder; Lithium
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.
chronic depression; remission; psychotherapy; antidepressant medications; combined treatments
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.
Recurrent Depression; Cognitive Therapy; Personality; Interpersonal Style; Therapeutic Alliance
Compared to nonanxious depressed patients, anxious depressed patients respond less to pharmacotherapy, prompting consideration of alternate treatments. Based on the transdiagnostic principles of cognitive therapy (CT), we predicted that anxious depressed patients would respond as well to CT as nonanxious depressed patients.
Adults (n = 523) with recurrent major depressive disorder received 12–14 weeks of CT as part of the Continuation Phase Cognitive Therapy Relapse Prevention Trial. Anxious depressed patients (n = 264; 50.4%) were compared to nonanxious depressed patients (n = 259; 49.6%) on demographic variables, initial severity, attrition, and rates and patterns of response and remission.
Anxious depressed patients presented with greater illness severity and had significantly lower response (55.3 vs. 68.3%) and remission rates (26.9 vs. 40.2%) based on clinician-administered measures. By contrast, smaller between-group differences for attrition, and for response (59.1 vs. 64.9%) and remission (41.7 vs. 48.7%) rates on self-report measures were not significant. Further, anxious depressed patients had greater speed of improvement on self-reported anxiety symptom severity and clinician-rated depressive and anxiety symptom severity measures.
Consistent with prior reports, anxious depressed patients presented with greater severity and, following CT, had lower response and remission rates on clinician-administered scales. However, anxious depressed patients improved more rapidly and response and remission rates on self-report measures were not significantly different from nonanxious depressed patients. Our findings suggest that anxious depressed patients may simply need additional time or more CT sessions to reach outcomes fully comparable to those of less anxious patients.
Cognitive therapy; Major depressive disorder; Anxious depression; Treatment outcome
Psychosocial interventions are effective adjuncts to pharmacotherapy in delaying recurrences of bipolar disorder; however, to date their effects on life functioning have been given little attention. In a randomized trial, the authors examined the impact of intensive psychosocial treatment plus pharmacotherapy on the functional outcomes of patients with bipolar disorder over the 9 months following a depressive episode.
Participants were 152 depressed outpatients with bipolar I or bipolar II disorder in the multisite Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. All patients received pharmacotherapy. Eighty-four patients were randomly assigned to intensive psychosocial intervention (30 sessions over 9 months of interpersonal and social rhythm therapy, cognitive behavior therapy [CBT], or family-focused therapy), and 68 patients were randomly assigned to collaborative care (a 3-session psychoeducational treatment). Independent evaluators rated the four subscales of the Longitudinal Interval Follow-Up Evaluation–Range of Impaired Functioning Tool (LIFE-RIFT) (relationships, satisfaction with activities, work/role functioning, and recreational activities) through structured interviews given at baseline and every 3 months over a 9-month period.
Patients in intensive psychotherapy had better total functioning, relationship functioning, and life satisfaction scores over 9 months than patients in collaborative care, even after pretreatment functioning and concurrent depression scores were covaried. No effects of psychosocial intervention were observed on work/role functioning or recreation scores during this 9-month period.
Intensive psychosocial treatment enhances relationship functioning and life satisfaction among patients with bipolar disorder. Alternate interventions focused on the specific cognitive deficits of individuals with bipolar disorder may be necessary to enhance vocational functioning after a depressive episode.
The role of antidepressants in bipolar disorder is controversial, and the comparative effectiveness of specific drugs is insufficiently studied. We report here a comparison of monoamine oxidase inhibitors (MAOI) with the serotonin reuptake inhibitor paroxetine (PAROX).
We conducted a retrospective analysis of data from a larger study, using the first antidepressant trial administered either after entry (n = 46) or after a recurrent episode during study participation (n = 6). Twenty two patients were treated with PAROX and 30 with MAOI. Durable recovery was determined from Hamilton depression and Young mania scores, based on published criteria.
PAROX treatment led to durable recovery in 27% of patients, a result very similar to the 24% recovery rate found in a recent STEP-BD trial. In contrast, patients treated with MAOI had a 53% durable recovery rate. Survival analysis showed a significantly faster recovery with MAOI (χ2 = 4.77, p = 0.029). Among subjects who were able to complete an adequate treatment trial of at least four weeks duration, durable recovery was attained in a significantly greater proportion of those treated with MAOI (16 of 23, 70%) as compared to PAROX (6 of 18, 33%)(Fisher's Exact Test, p = 0.023).
In these patients with bipolar depression, the antidepressant effectiveness of PAROX was unacceptably low, but rates of recovery with MAOI were significantly higher.
antidepressive agents; bipolar disorder; depressive disorder; clinical trial; monoamine oxidase inhibitors; treatment outcome
We developed models of Specialized Care for Bipolar Disorder (SCBD) and a psychosocial treatment [Enhanced Clinical Intervention (ECI)] that is delivered in combination with SCBD. We investigated whether SCBD and ECI + SCBD are able to improve outcomes and reduce health disparities for young and elderly individuals, African Americans, and rural residents with bipolar disorder.
Subjects were 463 individuals with bipolar disorder, type I, II, or not otherwise specified, or schizoaffective disorder, bipolar type, randomly assigned to SCBD or ECI + SCBD and followed longitudinally for a period of one to three years at four clinical sites.
Both treatment groups significantly improved over time, with no significant differences based on age, race, or place of residence, except for significantly greater improvement among elderly versus adult subjects. Improvement in quality of life was greater in the ECI + SCBD group. Of the 299 participants who were symptomatic at study entry, 213 achieved recovery within 24 months, during which 86 of the 213 subjects developed a new episode. No significant difference was found for race, place of residence, or age between the participants who experienced a recurrence and those who did not. However, the adolescent patients were less likely than the adult and elderly patients to experience a recurrence.
This study demonstrated the effectiveness of SCBD and the additional benefit of ECI independent of age, race, or place of residence. It also demonstrated that new mood episodes are frequent in individuals with bipolar disorder who achieve recovery and are likely to occur in spite of specialized, guideline-based treatments.
bipolar disorder; health disparities; outcomes; randomized trial
During a multisite, NIMH-sponsored clinical trial entitled, “Research Evaluating the Value of Augmentation of Medication by Psychotherapy” (REVAMP), we assessed the adequacy of prior antidepressant treatment in patients with chronic forms of major depressive disorder using the Antidepressant Treatment History Form (ATHF). We hypothesized that when compared to earlier studies treatment adequacy would not have increased over the past decade.
We found that only 33% of the 801 subjects enrolled had ever had a prior adequate trial of antidepressant medication. Patients significantly more likely to have received prior adequate antidepressant trials were older, married, white, had a longer duration of illness, had more melancholic features or met criteria for the melancholic subtype or met lifetime criteria for panic disorder.
The hypothesis that rates of treatment adequacy have not significantly increased over the past decade was supported. These results and the consistency of similar results over time point to the dire need for patient and provider education regarding the signs and symptoms of depression and its treatment.
Depression; Chronic; Treatment; Pharmacotherapy
Previous studies have found that few chronically depressed patients remit with antidepressant medications alone.
To determine the role of adjunctive psychotherapy in the treatment of chronically depressed patients with less than complete response to an initial medication trial.
This trial compared 12 weeks of (1) continued pharmacotherapy and augmentation with cognitive behavioral analysis system of psychotherapy (CBASP), (2) continued pharmacotherapy and augmentation with brief supportive psychotherapy (BSP), and (3) continued optimized pharmacotherapy (MEDS) alone. We hypothesized that adding CBASP would produce higher rates of response and remission than adding BSP or continuing MEDS alone.
Eight academic sites.
Chronically depressed patients with a current DSM-IV–defined major depressive episode and persistent depressive symptoms for more than 2 years.
Phase 1 consisted of open-label, algorithm-guided treatment for 12 weeks based on a history of antidepressant response. Patients not achieving remission received next-step pharmacotherapy options with or without adjunctive psychotherapy (phase 2). Individuals undergoing psychotherapy were randomized to receive either CBASP or BSP stratified by phase 1 response, ie, as nonresponders (NRs) or partial responders (PRs).
Main Outcome Measures
Proportions of remitters, PRs, and NRs and change on Hamilton Scale for Depression (HAM-D) scores.
In all, 808 participants entered phase 1, of which 491 were classified as NRs or PRs and entered phase 2 (200 received CBASP and MEDS, 195 received BSP and MEDS, and 96 received MEDS only). Mean HAM-D scores dropped from 25.9 to 17.7 in NRs and from 15.2 to 9.9 in PRs. No statistically significant differences emerged among the 3 treatment groups in the proportions of phase 2 remission (15.0%), partial response (22.5%), and non-response (62.5%) or in changes on HAM-D scores.
Although 37.5% of the participants experienced partial response or remitted in phase 2, neither form of adjunctive psychotherapy significantly improved outcomes over that of a flexible, individualized pharmacotherapy regimen alone. A longitudinal assessment of later-emerging benefits is ongoing.
clinicaltrials.gov Identifier: NCT00057551
The current report describes individuals with bipolar disorder who attempted or completed suicide while participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.
Baseline and course features of individuals with suicide events are described.
Among the 4360 people with bipolar disorder enrolled, 182 individuals made 270 prospectively observed suicidal acts, including 8 completed suicides. This represents a suicide rate of .014 per 100 person years in STEP-BD, which included frequent clinical visits, evidence based care, and standardized assessment at each patient contact. Approximately 1/3 of those who attempted suicide had more than one attempt during study participation. Those who completed suicide tended to do so early in study participation, and half of them did so on their first attempt.
While this study is limited to description of individuals and precipitants of completed suicides and attempts in STEP-BD, further analyses are planned to explore risk factors and potential interventions for prevention of suicidal acts in persons with bipolar disorder.
Persons with bipolar disorder are at high risk for suicide. Overall rates of suicide events in STEP-BD were lower than expected, suggesting that the combination of frequent clinical visits (i.e., access to care), standardized assessment, and evidence-based treatment were helpful in this population.
bipolar disorder; suicide; suicide attempt
We describe the development and psychometric properties of a new measure called the Skills of Cognitive Therapy (SoCT) in depressed adults and their cognitive therapists. The eight-item SoCT assesses patients' understanding and use of basic cognitive therapy (CT) skills rated from the perspectives of both observers (SoCT-O; therapists in this report) and patients (SoCT-P). Ratings of patients’ skill usage are made on 5-point Likert-type scales ranging from 1 ("never") to 5 ("always or when needed”). Higher scores reflect greater patient skill in applying cognitive therapy principles and coping strategies. To develop this scale, we used a 33-item pool, rated by both patients and their therapists at the middle and end of CT (Ns = 359–416), and evaluated the reliability and concurrent and predictive validity of both versions of the scale. The SoCT has excellent internal consistency reliability and moderate correlations between the observer and patient versions. Importantly, the SoCT showed good predictive validity for response when collected at the midpoint of acute phase CT. Considering both patients’ self-ratings and clinicians’ SoCT ratings, the odds ratio for responding to CT was 2.6. We discuss the practical utility of the SoCT, as well as its theoretical importance in research of patient CT skills (e.g., acquisition, comprehension, and generalization) as putative moderators or mechanisms of symptom change in the therapy.
cognitive therapy; depression; skill comprehension and use; assessment; mechanisms
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.
loss of antidepressant response; psychopharmacology; major depressive disorder; serotonin norepinephrine reuptake inhibitor; Rothschild Scale for Antidepressant Tachyphylaxis
Few studies have prospectively examined the relationships of sleep with symptoms and functioning in bipolar disorder.
The present study examined concurrent and prospective associations between total sleep time (TST) and sleep variability (SV) with symptom severity and functioning in a cohort of DSM-IV bipolar patients (N=468) participating in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), all of whom were recovered at study entry.
Concurrent associations at study entry indicated that shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity. Mixed-effects regression modeling was used to examine prospective associations in the 196 patients for whom follow-up data were available. Consistent with findings at study entry, shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity over 12 months.
These findings highlight the importance of disrupted sleep patterns in the course of bipolar illness.
Bipolar disorder; Sleep; Mania; Depression; Functioning; STEP-BD
Attenuation of protein kinase C (PKC) is a mechanism common to both established (lithium, valproate) and some novel (tamoxifen) antimanic agents. Verapamil, although primarily known as a calcium channel blocker, also has PKC inhibitory activity. Verapamil has shown antimanic activity in some but not all studies. Therefore, we investigated verapamil, used alone or as an adjunctive treatment, in manic patients who did not respond to an initial adequate trial of lithium.
Each study phase lasted three weeks. Subjects were treated openly with lithium in Phase 1 (n = 45). Those who failed to respond were randomly assigned to double-blind treatment in Phase 2 with either verapamil (n = 10) or continued-lithium (n = 8). Phase 2 nonresponders (n = 10) were assigned to combined verapamil/lithium in Phase 3.
Response in Phase 2 did not differ significantly between verapamil and continued-lithium. During Phase 3, response to combined treatment was significantly better than overall response to monotherapy in Phase 2 (Fisher’s Exact test, p = 0.043). Mania ratings improved during combined treatment in Phase 3 by 88.2% (linear mixed model analysis, F = 4.34, p = 0.013), compared with 10.5% improvement during Phase 2.
In this preliminary investigation, verapamil monotherapy did not demonstrate antimanic efficacy. By contrast, the combination of verapamil plus lithium was highly efficacious. Our findings thus suggest that verapamil may have potential utility as an adjunct to lithium. This effect may be mediated by additive actions on PKC inhibition, which may be an important mechanism for antimanic agents in general.
antimanic; bipolar disorder; lithium; mania; protein kinase C; verapamil
Recent studies demonstrate the poor psychosocial outcomes associated with bipolar disorder. Occupational functioning, a key indicator of psychosocial disability, is often severely affected by the disorder. The authors describe the effect of acute treatment with interpersonal and social rhythm therapy on occupational functioning over a period of approximately 2.5 years.
Patients with bipolar I disorder were randomly assigned to receive either acute and maintenance interpersonal and social rhythm therapy, acute and maintenance intensive clinical management, acute interpersonal and social rhythm therapy and maintenance intensive clinical management, or acute intensive clinical management and maintenance interpersonal and social rhythm therapy, all with appropriate pharmacotherapy. Occupational functioning was measured with the UCLA Social Attainment Scale at baseline, at the end of acute treatment, and after 1 and 2 years of maintenance treatment.
The main effect of treatment did not reach conventional levels of statistical significance; however, the authors observed a significant time by initial treatment interaction. Participants initially assigned to interpersonal and social rhythm therapy showed more rapid improvement in occupational functioning than those initially assigned to intensive clinical management, primarily accounted for by greater improvement in occupational functioning during the acute treatment phase. At the end of 2 years of maintenance treatment, there were no differences between the treatment groups. A gender effect was also observed, with women who initially received interpersonal and social rhythm therapy showing more marked and rapid improvement. There was no effect of maintenance treatment assignment on occupational functioning outcomes.
In this study, interpersonal and social rhythm therapy, with its emphasis on amelioration of interpersonal and role functioning, improved occupational functioning significantly more rapidly than did a psychoeducational and supportive approach with no such emphasis on functional capacities.
The association between cocaine use and depression has been frequently observed. However, less is known about the significance of depression in the treatment of cocaine use disorders. This study examined possible interrelations between drug use and depression severity among cocaine-dependent patients in psychosocial treatments for cocaine dependence.
Monthly assessed drug use and depression severity scores of N = 487 patients during 6-month psychosocial treatments for cocaine dependence were analyzed using hybrid latent growth models.
Results indicated a moderate but statistically significant (z = 3.13, p < .01) influence of depression severity on increased drug use in the upcoming month, whereas drug use did not affect future depression severity.
Findings suggest that depression symptoms are an important predictor of drug use outcomes during psychosocial treatments for cocaine dependence and, hence, underline the importance of adequately addressing depression symptoms to improve treatment outcomes.
Cocaine Dependence; Depression; Psychosocial Treatment; Interrelations; Hybrid Latent Growth Models
Bipolar depression is more common, disabling, and difficult-to-treat than the
manic and hypomanic phases that define bipolar disorder. Unlike the treatment of
so-called “unipolar” depressions, antidepressants generally are
not indicated as monotherapies for bipolar depressions and recent studies
suggest that -even when used in combination with traditional mood stabilizers
– antidepressants may have questionable value for bipolar depression. The
current practice is that mood stabilizers are initiated first as monotherapies;
however, the antidepressant efficacy of lithium and valproate is modest at best.
Within this context the role of atypical antipsychotics is being evaluated. The
combination of olanzapine and the antidepressant fluoxetine was the first
treatment to receive regulatory approval in the US specifically for bipolar I
depression. Quetiapine was the second medication to be approved for this
indication, largely as the result of two pivotal trials known by the acronyms of
BOLDER (BipOLar DEpRession) I and II. Both studies demonstrated that two doses
of quetiapine (300 mg and 600 mg given once daily at bedtime) were significantly
more effective than placebo, with no increased risk of patients switching into
mania. Pooling the two studies, quetiapine was effective for both bipolar I and
bipolar II depressions and for patients with (and without) a history of rapid
cycling. The two doses were comparably effective in both studies. Although the
efficacy of quetiapine monotherapy has been established, much additional
research is necessary. Further studies are needed to more fully investigate
dose-response relationships and comparing quetiapine monotherapy to other mood
stabilizers (lithium, valproate, and lamotrigine) in bipolar depression, both
singly and in combination. Head-to-head studies are needed comparing quetiapine
to the olanzapine-fluoxetine combination. Longer-term studies are needed to
confirm the persistence of response and to better gauge effects on metabolic
profiles across months of therapy. A prospective study of patients specifically
seeking treatment for rapid cycling and those with a history of
treatment-emergent affective shifts also is needed. Despite the caveats, as
treatment guidelines are revised to incorporate new data, the efficacy and
tolerability of quetiapine monotherapy must be given serious consideration.
bipolar disorder; manic depression; depression; quetiapine; mood stabilizer
Some individuals with bipolar disorder transition directly from major depressive episodes to manic, hypomanic, or mixed states during treatment, even in the absence of antidepressant treatment. Prevalence and risk factors associated with such transitions in clinical populations are not well established, and were examined in the Systematic Treatment Enhancement Program for Bipolar Disorder study, a longitudinal cohort study. Survival analysis was used to examine time to transition to mania, hypomania, or mixed state among 2166 bipolar I and II individuals in a major depressive episode. Cox regression was used to examine baseline clinical and sociodemographic features associated with hazard for such a direct transition. These features were also examined for interactive effects with antidepressant treatment. In total, 461/2166 subjects in a major depressive episode (21.3%) transitioned to a manic/hypomanic or mixed state before remission, including 289/1475 (19.6%) of those treated with antidepressants during the episode. Among the clinical features associated with greatest transition hazard were greater number of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants. Greater manic symptom severity was also associated with risk for manic transition among both antidepressant-treated and antidepressant-untreated individuals. Three features, history of suicide attempt, younger onset age, and bipolar subtype, exhibited differential effects between individuals treated with antidepressants and those who were not. These results indicate that certain clinical features may be associated with greater risk of transition from depression to manic or mixed states, but the majority of them are not specific to antidepressant-treated patients.
bipolar disorder; mania; switch; antidepressant; adverse effect; clinical pharmacology; clinical trials; depression, unipolar; bipolar; mood; anxiety; stress disorders; psychopharmacology; antidepressant; switch; bipolar disorder