Systemic challenges in bipolar disorder management: A patient-centered approach.

OBJECTIVES: As part of a series of Patient-Centered Outcomes Research Institute-funded large-scale retrospective observational studies on bipolar disorder (BD) treatments and outcomes, we sought the input of patients with BD and their family members to develop research questions. We aimed to identify systemic root causes of patient-reported challenges with BD management in order to guide subsequent studies and initiatives. METHODS: Three focus groups were conducted where patients and their family members (total n = 34) formulated questions around the central theme, "What do you wish you had known in advance or over the course of treatment for BD?" In an affinity mapping exercise, participants clustered their questions and ranked the resulting categories by importance. The research team and members of our patient partner advisory council further rated the questions by expected impact on patients. Using a Theory of Constraints systems thinking approach, several causal models of BD management challenges and their potential solution were developed with patients using the focus group data. RESULTS: A total of 369 research questions were mapped to 33 categories revealing 10 broad themes. The top priorities for patient stakeholders involved pharmacotherapy and treatment alternatives. Analysis of causal relationships underlying 47 patient concerns revealed two core conflicts: for patients, whether or not to take pharmacotherapy, and for mental health services, the dilemma of care quality vs quantity. CONCLUSIONS: To alleviate the core conflicts identified, BD management requires a coordinated multidisciplinary approach including: improved access to mental health services, objective diagnostics, sufficient provider visit time, evidence-based individualized treatment, and psychosocial support.

Negative affect predicts adults' ratings of the current, but not childhood, impact of adverse childhood events.

Adverse childhood events (ACE's) have been empirically related to a wide range of negative health and mental health outcomes. However, not all individuals who experience ACE's follow a trajectory of poor outcomes, and not all individuals perceive the impact of ACE's as necessarily negative. The purpose of this study was to investigate positive and negative affect as predictors of adults' ratings of both the childhood and adult impact of their childhood adversity. Self-report data on ACE experiences, including number, severity, and 'impact' were collected from 158 community members recruited on the basis of having adverse childhood experiences. Results indicated that, regardless of event severity and number of different types of adverse events experienced, high levels of negative affect were the strongest predictor of whether the adult impact of the adverse childhood events was rated as negative. All individuals rated the childhood impact of events the same. Implications are discussed.

The importance of anxiety in both major depression and bipolar disorder.

BACKGROUND: Generalized anxiety disorder (GAD) is frequently co-morbid with major depression (MDD), and this becomes more so when the duration requirement is relaxed. Both anxiety diagnoses and anxious symptoms are more common in both unipolar and bipolar depression. This paper explores the relationship between anxious symptoms and GAD with both unipolar and bipolar depression. METHOD: MDD and bipolar disorder (BPD) are compared in three important respects: the extent of their co-morbidity with anxious symptoms and GAD, the effects that anxiety has on outcome of MDD and BPD, and the effects that anxiety has on the probability of suicide in each disorder. RESULTS: Anxious diagnoses occur frequently in association with depressive disorders, albeit to a different extent in the various subtypes of depression. In both disorders, anxiety affects the outcome and makes suicidal thoughts, and completed suicide more likely. CONCLUSIONS: Anxious phenomena should be assessed whenever a depressive disorder is diagnosed. It is likely that the raised expectancy of anxious phenomena is related to an individual's premorbid level of negative affect, and it is possible that suicidal phenomena are related to subthreshold hypomanic symptoms.

Case report on the management of depression in schizoaffective disorder, bipolar type focusing on lithium levels and measurement-based care.

There is little evidence supporting the management of depression in schizoaffective disorder, bipolar type. Managing bipolar depression can be a daunting task for clinicians. Most bipolar patients spend 80% of their time in the depressive phase of illness. In contrast with full-blown mania, patients and family frequently fail to recognize bipolar depression, which may interfere with early diagnosis and treatment. With only a few medications approved for bipolar depression, treatment becomes very challenging. There is evidence to support that schizoaffective depression has a worse outcome than psychotic depression and nonpsychotic depression. We report a patient with schizoaffective disorder, bipolar type with severe depression who responded to an adequate level of lithium and subsequently, on a combination of lithium and quetiapine. Finally, we emphasize the importance of measurement-based care. To our knowledge, this is the first case report focusing on the management of depression in schizoaffective disorder, bipolar type.

An overview of mood disorders in the DSM-5.

The process of revising the DSM, which is based on new findings in the literature and experience with the current classification, is initiated every 12-18 years. The process for the revision of DSM-IV to the DSM-5 began in 2006-after a series of meeting proceedings and monographs were published during the previous 3 years-with the appointment of diagnostic group chairs by Director Dr. David Kupfer and Vice Director Dr. Darrel Regier. Members were recruited for workgroups to review the existing DSM-IV, to decide what worked well and which areas needed change, to review the available literature and data, and to propose changes based on an appropriate level of evidence in the literature proportional to the significance of the change. At the halfway point in this process, the Mood Disorders Workgroup has made tentative recommendations to be tested in field trials. These recommendations and some of the basis for them are discussed in this review. Final decisions await the data from field trials, possible revisions by the workgroups, and action by the task force. This article describes some of the recommendations made by the Mood Disorders Workgroup at this point in the process.

Antidepressant drug effects and depression severity: a patient-level meta-analysis.

CONTEXT: Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression. OBJECTIVE: To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression. DATA SOURCES: PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews. STUDY SELECTION: Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included. DATA EXTRACTION: Individual patient-level data were obtained from study authors. RESULTS: Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. CONCLUSIONS: The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral Therapy: Phase 2 of a 2-Phase Randomized Clinical Trial.

Importance: Antidepressant medication (ADM) maintenance treatment is associated with the prevention of depressive recurrence in patients with major depressive disorder (MDD), but whether cognitive behavioral therapy (CBT) treatment is associated with recurrence prevention remains unclear. Objective: To determine the effects of combining CBT with ADM on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with MDD. Design, Setting, and Participants: A total of 292 adult outpatients with chronic or recurrent MDD who participated in the second phase of a 2-phase trial. Participants had recovered in the first phase of the trial receiving ADM, either alone or in combination with CBT. The trial was conducted in research clinics in 3 university medical centers in the United States. Patients in phase 2 were randomized to receive maintenance of or withdrawal from ADM and were followed up for 3 years. The first and last patients entered phase 2 in August 2003 and October 2009, respectively. The last patient completed phase 2 in August 2012. Data were analyzed from December 2013 to December 2018. Interventions: Maintenance of or withdrawal from treatment with ADM. Main Outcomes and Measures: Recurrence of an MDD episode using longitudinal interval follow-up evaluations; sustained recovery across both phases. Results: A total of 292 participants (171 women, 121 men; mean [SD] age 45.1 [12.9] years) were included in analyses of depressive recurrence. Maintenance ADM yielded lower rates of recurrence compared with ADM withdrawal regardless of whether patients had achieved recovery in phase 1 with ADM alone (48.5% vs 74.8%; z = -3.16; P = .002; number needed to treat [NNT], 2.8; 95% CI, 1.8-7.0) or ADM plus CBT (48.5% vs 76.7%; z = -3.49; P < .001; NNT, 2.7; 95% CI, 1.9-5.9). Sustained recovery rates differed as a function of phase 2 condition, with maintenance ADM superior to ADM withdrawal (z = 2.90; P = .004; OR, 2.54; 95% CI, 1.37-4.84; NNT, 2.3; 95% CI, 1.5-6.4). Phase 1 condition was not associated with differential rates of sustained recovery (ADM alone vs ADM plus CBT; z = 0.22; P = .83; OR, 1.08; 95% CI, 0.52-2.11; NNT, 26.0; 95% CI, number needed to harm 3.2 to NNT 2.8), nor was there a significant interaction of phase 1 condition and phase 2 condition (z = 0.30; P = .77; OR, 1.14; 95% CI, 0.49-2.88). Conclusions and Relevance: Maintenance ADM treatment, but not previous exposure to CBT, was associated with reduced rates of depressive recurrence. In previous studies, when CBT has been provided without ADM, CBT has shown a preventive effect on depressive relapse. Whether CBT also has a preventive effect on depressive recurrence, or if adding ADM interferes with any such preventive effect, remains unclear. Trial Registration: ClinicalTrial.gov identifier: NCT00057577.

Ecological studies of antidepressant treatment and suicidal risks.

Ongoing discussion of potential benefits and risks of antidepressant treatment with respect to suicidal behaviors includes many ecological, or population-based, correlational studies of temporal or regional trends in suicide rates and rates of usage of modern antidepressants including serotonin-reuptake inhibitors (SRIs). Since this body of research has not been compiled and evaluated, we used computerized literature searching to identify 19 relevant published studies. They yielded heterogeneous findings: only 8/19 found significant inverse correlations between rising sales of modern antidepressants in the 1990 s and falling suicide rates not anticipated in the 1980s. Average reductions in suicide rates in the 1990 s (10.7%) and 1980s (10.0%) differed little in 11 studies with data from both eras. Reduction of suicide rates in the 1990 s was unrelated to geographic region, population size, units of analysis, publication year, or growth in antidepressant usage, but was greater with higher initial suicide rates, in men, and in older persons. In the same decade, suicides rates decreased in only half of 79 large countries. Overall, these findings yield limited and inconsistent support for the hypothesis that increased use of modern antidepressants might limit suicide risk, and no evidence that the risk increased. Suicidal risk is determined by complex factors, including access to clinical services, in general, and more comprehensive treatment of depression, in particular. Overall, as with findings from randomized trials and cohort or case-control studies, evidence of specific antisuicidal effects of antidepressant treatment from ecological analyses remains elusive.

ACNP Task Force report on SSRIs and suicidal behavior in youth.

This Task Force report by the American College of Neuropsychopharmacology evaluates the safety and efficacy of selective serotonin reuptake inhibitor (SSRIs) antidepressants for depressed youth under 18 years. The report was undertaken after regulatory agencies in the United States and United Kingdom raised concerns in 2003 about the possibility that treatment of depression in children and adolescents with SSRIs may increase the risk of suicidal thinking or suicide attempts.

Self-reported depressive symptom measures: sensitivity to detecting change in a randomized, controlled trial of chronically depressed, nonpsychotic outpatients.

This study evaluated and compared the performance of three self-report measures: (1) 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR30); (2) 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and (3) Patient Global Impression-Improvement (PGI-I) in assessing clinical outcomes in depressed patients during a 12-week, acute phase, randomized, controlled trial comparing nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), and the combination in the treatment of chronic depression. The IDS-SR30, QIDS-SR16, PGI-I, and the 24-item Hamilton Depression Rating Scale (HDRS24) ratings were collected at baseline and at weeks 1-4, 6, 8, 10, and 12. Response was defined a priori as a > or =50% reduction in baseline total score for the IDS-SR30 or for the QIDS-SR16 or as a PGI-I score of 1 or 2 at exit. Overall response rates (LOCF) to nefazodone were 41% (IDS-SR30), 45% (QIDS-SR16), 53% (PCI-I), and 47% (HDRS17). For CBASP, response rates were 41% (IDS-SR30), 45% (QIDS-SR16), 48% (PGI-I), and 46% (HDRS17). For the combination, response rates were 68% (IDS-SR30 and QIDS-SR16), 73% (PGI-I), and 76% (HDRS17). Similarly, remission rates were comparable for nefazodone (IDS-SR30=32%, QIDS-SR16=28%, PGI-I=22%, HDRS17=30%), for CBASP (IDS-SR30=32%, QIDS-SR16=30%, PGI-I=21%, HDRS17=32%), and for the combination (IDS-SR30=52%, QIDS-SR16=50%, PGI-I=25%, HDRS17=49%). Both the IDS-SR30 and QIDS-SR16 closely mirrored and confirmed findings based on the HDRS24. These findings raise the possibility that these two self-reports could provide cost- and time-efficient substitutes for clinician ratings in treatment trials of outpatients with nonpsychotic MDD without cognitive impairment. Global patient ratings such as the PGI-I, as opposed to specific item-based ratings, provide less valid findings.

Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression.

BACKGROUND: Although various strategies have been proposed to treat antidepressant nonresponders, little controlled research has been published that examines prospectively the use of switching to an alternate antidepressant. METHODS: This was a multisite study in which outpatients with chronic major depression (with or without concurrent dysthymia), who failed to respond to 12 weeks of double-blind treatment with either sertraline hydrochloride (n = 117) or imipramine hydrochloride (n = 51), were crossed over or switched to 12 additional weeks of double-blind treatment with the alternate medication. Outcome measures included the 24-item Hamilton Rating Scale for Depression and the Clinical Global Impressions--Severity and Improvement scales. RESULTS: The switch from sertraline to imipramine (mean dosage, 221 mg/d) and from imipramine to sertraline (mean dosage, 163 mg/d) resulted in clinically and statistically significant improvements. The switch to sertraline treatment was associated with fewer adverse effect complaints and significantly less attrition owing to adverse effects. Although sertraline treatment also resulted in significantly higher response rates in the intent-to-treat samples (60% in the sertraline group and 44% in the imipramine group), neither the intent-to-treat remission rates nor the response and remission rates among study completers differed significantly. Moreover, after considering the effect of attrition, there were no significant treatment effects on the more comprehensive generalized estimating equation analyses of the continuous dependent measures. CONCLUSIONS: More than 50% of chronically depressed antidepressant nonresponders benefited from a switch from imipramine to sertraline, or vice versa, despite a high degree of chronicity. As in the initial trial, sertraline was generally better tolerated than imipramine. Switching to a standard antidepressant of a different class is a useful treatment strategy for antidepressant nonresponders and could be considered a standard of comparison for future studies of novel alternate strategies.

When should a trial of fluoxetine for major depression be declared failed?

OBJECTIVE: Although the newer antidepressants are widely used, little is known about how long it takes to see their full effect. The authors sought to determine how many weeks a fluoxetine trial with no improvement should continue before treatment is changed. METHOD: The data involved 840 patients in a 12-week open trial of fluoxetine, 20 mg/day, followed by a blinded, placebo-controlled discontinuation study. Outcomes at 4, 6, 8, 10, and 12 weeks were classified as nonresponse, partial response, response, and remission and were based on Hamilton Depression Rating Scale scores. The rate of remission at week 12 was calculated for each group of patients without remission at the earlier time points. The time to relapse during weeks 13-26 of the discontinuation study was examined in patients taking placebo and fluoxetine in relation to status at week 6. RESULTS: Patients unimproved at week 6 had a remission rate at week 12 of 31%-41%. For patients with remission at week 12, level of improvement at week 6 did not affect prognosis in weeks 13-26. Of the unimproved patients at week 8, 23% had remissions by week 12. The week 12 remission rate for unimproved patients at week 4 was clearly high enough to justify continued treatment; the rate for unimproved patients at week 10 was too low. CONCLUSIONS: These data suggest that nonresponse to fluoxetine should not be declared until 8 weeks of treatment have elapsed. Practitioners should discuss trial length with patients at the beginning of treatment.

Lithium combinations in acute and maintenance treatment of unipolar and bipolar depression.

Bipolar illness and unipolar depression are both affective disorders associated with high lifetime morbidity and premature mortality due to suicide. Numerous double-blind, placebo-controlled trials have shown that lithium augmentation therapy is effective in treating acute episodes of bipolar depression, refractory major depression, and delusional depression as well as in reducing recurrences of these illnesses. Lithium is the only agent approved by the U.S. Food and Drug Administration for maintenance treatment of bipolar disorder. Further research is needed to specifically address whether the antidepressant effect of adding lithium is greater in bipolar disorder or in unipolar depressions. This article will summarize available evidence and clinical considerations regarding the use of lithium augmentation in acute and maintenance treatment of unipolar and bipolar depressions.

Clinical correlates of inpatient suicide.

BACKGROUND: Previous suicide assessment research has led to standard predictors of risk. Despite this, there are approximately 30,000 suicides per year in the United States, 5% to 6% of which occur in hospitals. The primary purpose of this study is to improve our ability to assess risk and intervene successfully. METHOD: Charts from 76 patients who committed suicide while in the hospital, or immediately after discharge, were reviewed. The week before suicide was rated for both standard risk predictors and, using items from the Schedule for Affective Disorders and Schizophrenia (SADS), for presence and severity of symptoms found to be correlated with acute risk in recent studies. RESULTS: Regarding standard predictors, only 49% (N = 37) had any prior suicide attempt and 25% (N = 19) were admitted for this reason. Thirty-nine percent (30/76) were admitted for suicidal ideation, but 78% denied suicidal ideation at their last communication about this; 46% (N = 35) showed no evidence of psychosis; of those on precautions (N = 45), 51% (N = 23) were on q 15 minute suicide checks or 1:1 observation; and 28% (N = 21) had a no-suicide contract in effect. On SADS ratings, 79% (N = 60) met criteria for severe or extreme anxiety and/or agitation. CONCLUSION: Standard risk assessments and standard precautions used were of limited value in protecting this group from suicide. Adding severity of anxiety and agitation to our current assessments may help identify patients at acute risk and suggest effective treatment interventions. The importance of a matched comparison group to ascertain if this sample can be blindly discriminated from inpatients who do not commit suicide is clear.

Fluoxetine and norfluoxetine plasma concentrations during relapse-prevention treatment.

BACKGROUND: Virtually no attention has been given to the relationship between antidepressant plasma drug concentrations and relapse-prevention during maintenance therapy. The purpose of this study was to investigate the relationship between steady-state plasma drug concentrations and outcome during relapse-prevention therapy with fluoxetine. METHODS: The patients studied had responded to acute fluoxetine treatment for major depression (defined by DSM-III-R). Patients who met criteria for remission after 10-12 weeks of open-label acute fluoxetine therapy (N=395 of 839 patients), were randomly assigned to one of four treatment arms (50 weeks of fluoxetine, 38 weeks of fluoxetine followed by 12 weeks of placebo, 14 weeks of fluoxetine followed by 36 weeks of placebo and 50 weeks of placebo). Plasma fluoxetine and norfluoxetine concentrations were measured (1) after 4 and 8 weeks of open-label treatment and (2) at the beginning and after 14 weeks of double-blind, relapse-prevention therapy. RESULTS: Mean drug plasma levels were stable throughout the study. There was no significant difference in steady state plasma levels for the patients who relapsed compared to those who completed fluoxetine therapy without relapsing after 14, 38 or 50 weeks of fluoxetine relapse-prevention treatment. In addition, time-to-relapse was not related to steady-state drug plasma levels. Finally, after dividing patients into two groups based on their drug plasma levels, no significant differences were seen in the cumulative proportions of patients staying well during relapse-prevention therapy. DISCUSSION: Plasma concentrations of fluoxetine and/or its metabolite norfluoxetine, are not correlated with relapse in patients treated with a fixed dose of 20 mg/day fluoxetine. Fluoxetine plasma levels cannot be used to guide relapse-prevention treatment.

Prognostic models to detect and monitor the near-term risk of suicide: state of the science.

Aspirational Goal 3 of the National Action Alliance for Suicide Prevention's Research Prioritization Task Force research agenda is to "find ways to assess who is at risk for attempting suicide in the immediate future." Suicide risk assessment is the practice of detecting patient-level conditions that may rapidly progress toward suicidal acts. With hundreds of thousands of risk assessments occurring every year, this single activity arguably represents the most broadly implemented, sustained suicide prevention activity practiced in the U.S. Given this scope of practice, accurate and reliable risk assessment capabilities hold a central and irreplaceable position among interventions mounted as part of any public health approach to suicide prevention. Development of more reliable methods to detect and measure the likelihood of impending suicidal behaviors, therefore, represents one of the more substantial advancements possible in suicide prevention science today. Although past "second-generation" risk models using largely static risk factors failed to show predictive capabilities, the current "third-generation" dynamic risk prognostic models have shown initial promise. Methodologic improvements to these models include the advent of real-time, in vivo data collection processes, common data elements across studies and data sharing to build knowledge around key factors, and analytic methods designed to address rare event outcomes. Given the critical need for improved risk detection, these promising recent developments may well foreshadow advancement toward eventual achievement of this Aspirational Goal.