Publications by authors named "Andrew Nierenberg"

405 Publications

Statins: Neurobiological underpinnings and mechanisms in mood disorders.

Neurosci Biobehav Rev 2021 09 13;128:693-708. Epub 2021 Jul 13.

Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, VIC, Australia; Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia; Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia. Electronic address:

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Statins may therefore afford some therapeutic benefit in mood disorders. In this paper, we review the pathophysiology of mood disorders with a focus on pharmacologically relevant pathways, using major depressive disorder and bipolar disorder as exemplars. Statins are discussed in the context of these disorders, with particular focus on the putative mechanisms involved in their anti-inflammatory and immunomodulatory effects. Recent clinical data suggest that statins may have antidepressant properties, however given their interactions with many known biological pathways, it has not been fully elucidated which of these are the major determinants of clinical outcomes in mood disorders. Moreover, it remains unclear what the appropriate dose, or appropriate patient phenotype for adjunctive treatment may be. High quality randomised control trials in concert with complementary biological investigations are needed if the potential clinical effects of statins on mood disorders, as well as their biological correlates, are to be better understood.
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http://dx.doi.org/10.1016/j.neubiorev.2021.07.012DOI Listing
September 2021

Illness stage and predominant polarity in bipolar disorder: Correlation with burden of illness and moderation of treatment outcome.

J Psychiatr Res 2021 Aug 2;140:205-213. Epub 2021 Jun 2.

Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, 50 Staniford Street, Suite 580, Boston, MA, 02114, United States; Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, United States. Electronic address:

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.
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http://dx.doi.org/10.1016/j.jpsychires.2021.05.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319086PMC
August 2021

Development of a Patient-Centered Software System to Facilitate Effective Management of Bipolar Disorder.

Psychopharmacol Bull 2021 Mar;51(2):8-19

Bowden, M.D., Emeritus Professor, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas. Priesmeyer, PhD., Jurica Professor of Management, Department of Management and Marketing, St Mary's University, San Antonio, Texas. Tohen, M.D., Dr.P.H., M.B.A, University Distinguished Professor and Chairman, Department of Psychiatry and Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. Singh, M.D., Deceased. Calabrese, M.D., Director, Mood Disorders Program, UH Cleveland Medical Center Case Western Reserve University School of Medicine, Cleveland, Ohio. Ketter, M.D, Emeritus Professor, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California. Nierenberg, M.D., Director, Dauten Family Center for Bipolar Treatment Innovation Massachusetts General Hospital, Harvard Medical School. Thase, M.D., Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Gregg Siegel, M.S, Biomedical Development Corporation, San Antonio, Texas. Leslie H. Siegel, M.F.A, Biomedical Development Corporation, San Antonio, Texas. Mintz, PhD., Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas. Mallakh, M.D., Mood Disorders Research Program, Depression Center, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky. McElroy, M.D., Professor of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio. Martinez, M.D., Professor and Mary Avis Weir Chair in Psychiatry, Director, Adult Mood Disorders Program, Co-Director, Mind, Brain, and Behavior, Department of Psychiatry and Behavioral Sciences University of Texas Health Science Center San Antonio, San Antonio, Texas.

Objective: Self-management of bipolar disorder (BD) is an important component of treatment.

Methods: We developed a patient-centered computational software system based on concepts from nonlinear systems (chaos) theory with mobile access to assist in managing BD known as KIOS. KIOS tracks interacting symptoms to determine theprecise state of a BD patient. Once the patient's state is identified and the trajectory of the patient established, specific advice is generated to help manage the course of the disease. KIOS also provides analytics that can be used by clinicians and researchers to track outcomes and the course of illness. A 12-week field test was completed.

Results: In 20 BD subjects, use of KIOS was associated with improvements in primary symptom categories of BD. Usability and generated advice were rated as a median of 6 out of a maximum of 7.

Conclusions: The KIOS focus on change illuminates problems in the same way that humans experience them, implying that the future state will be consequent to changes made to impact the current state. Randomized clinical trial is indicated.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146566PMC
March 2021

Clinimetric Criteria for Patient-Reported Outcome Measures.

Psychother Psychosom 2021 26;90(4):222-232. Epub 2021 May 26.

Department of Psychiatry, University at Buffalo, State University of New York, Buffalo, New York, USA.

Patient-reported outcome measures (PROMs) are self-rated scales and indices developed to improve the detection of the patients' subjective experience. Given that a considerable number of PROMs are available, it is important to evaluate their validity and usefulness in a specific research or clinical setting. Published guidelines, based on psychometric criteria, do not fit in with the complexity of clinical challenges, because of their quest for homogeneity of components and inadequate attention to sensitivity. Psychometric theory has stifled the field and led to the routine use of scales widely accepted yet with a history of poor performance. Clinimetrics, the science of clinical measurements, may provide a more suitable conceptual and methodological framework. The aims of this paper are to outline the major limitations of the psychometric model and to provide criteria for clinimetric patient-reported outcome measures (CLIPROMs). The characteristics related to reliability, sensitivity, validity, and clinical utility of instruments are critically reviewed, with particular reference to the differences between clinimetric and psychometric approaches. Of note is the fact that PROMs, rating scales, and indices developed according to psychometric criteria may display relevant clinimetric properties. The present paper underpins the importance of the clini-metric methodology in choosing the appropriate PROMs. CLIPROM criteria may also guide the development of new indices and the validation of existing PROMs to be employed in clinical settings.
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http://dx.doi.org/10.1159/000516599DOI Listing
May 2021

An online intervention for increasing physical activity in individuals with mood disorders at risk for cardiovascular disease: Design considerations.

J Affect Disord 2021 08 2;291:102-109. Epub 2021 May 2.

Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Background: Physical activity can mitigate the risk of cardiovascular diseases, but the presence of mood disorders makes it challenging to follow or develop a regular exercise habit. We conducted an online comparative effectiveness study (Healthy Hearts Healthy Minds) to evaluate whether an online psychosocial intervention adjunctive to an activity monitor (Fitbit) can improve adherence to physical activity among individuals with mood disorders who have or are at-risk for cardiovascular disease (CVD).

Methods: In this paper, we explore design considerations (including both procedural challenges and achievements) of relevance to our study.

Results: Challenges of this study included navigating a complex IRB review process, integrating two study platforms, automating study procedures, and optimizing participant engagement. Achievements of this study included building trust with collaborators, leveraging existing online communities, generating daily data reports, and conducting patient-centered research.

Limitations: These design considerations are based on a single online comparative effectiveness study, and other online intervention studies may be presented with other unique challenges that are specific to their study format or aims. Consistent with some of the generalizability challenges facing other online studies, participants in this study were overall highly educated (most had at least a college degree).

Conclusions: We successfully conducted a large-scale virtual online intervention to increase physical activity of participants with comorbid mood and cardiovascular disorders by overcoming substantial operational and technical challenges. We hope that this exploration of design considerations in the context of our online study can inform upcoming online intervention studies.
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http://dx.doi.org/10.1016/j.jad.2021.04.094DOI Listing
August 2021

How to Evaluate Patients and Educate Them About Self-Examinations for Tardive Dyskinesia Between Appointments.

J Clin Psychiatry 2021 03 9;82(1). Epub 2021 Mar 9.

Dauten Family Center for Bipolar Treatment Innovation and the Depression Clinical and Research Program, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Boston.

Patients taking dopamine-blocking agents such as antipsychotics are at risk for developing tardive dyskinesia. In this webcast, Drs McEvoy and Nierenberg discuss symptoms of tardive dyskinesia, how to observe patients (whether in person or via telemedicine), and how to educate patients and families about TD.
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http://dx.doi.org/10.4088/JCP.NU19047WC6CDOI Listing
March 2021

Perceived helpfulness of treatment for specific phobia: Findings from the World Mental Health Surveys.

J Affect Disord 2021 06 20;288:199-209. Epub 2021 Apr 20.

Department of Health Care Policy, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Although randomized trials show that specific phobia treatments can be effective, it is unclear whether patients experience treatment as helpful in clinical practice. We investigated this issue by assessing perceived treatment helpfulness for specific phobia in a cross-national epidemiological survey.

Methods: Cross-sectional population-based WHO World Mental Health (WMH) surveys in 24 countries (n=112,507) assessed lifetime specific phobia. Respondents who met lifetime criteria were asked whether they ever received treatment they considered helpful and the number of professionals seen up to the time of receiving helpful treatment. Discrete-event survival analysis was used to calculate conditional-cumulative probabilities of obtaining helpful treatment across number of professionals seen and of persisting in help-seeking after prior unhelpful treatment.

Results: 23.0% of respondents reported receiving helpful treatment from the first professional seen, whereas cumulative probability of receiving helpful treatment was 85.7% after seeing up to 9 professionals. However, only 14.7% of patients persisted in seeing up to 9 professionals, resulting in the proportion of patients ever receiving helpful treatment (47.5%) being much lower than it could have been with persistence in help-seeking. Few predictors were found either of perceived helpfulness or of persistence in help-seeking after earlier unhelpful treatments.

Limitations: Retrospective recall and lack of information about either types of treatments received or objective symptomatic improvements limit results.

Conclusions: Despite these limitations, results suggest that helpfulness of specific phobia treatment could be increased, perhaps substantially, by increasing patient persistence in help-seeking after earlier unhelpful treatments. Improved understanding is needed of barriers to help-seeking persistence.
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http://dx.doi.org/10.1016/j.jad.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154701PMC
June 2021

Evidence-based versus clinical expertise guidelines for Bipolar Disorders.

Bipolar Disord 2021 Mar 8. Epub 2021 Mar 8.

Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1111/bdi.13071DOI Listing
March 2021

A surrogate measure for patient reported symptom remission in administrative data.

BMC Psychiatry 2021 03 4;21(1):121. Epub 2021 Mar 4.

Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.

Background: In real-world pragmatic administrative databases, patient reported remission is often missing.

Objective: We evaluate if, in administrative data, five features of antidepressant use patterns can replace patient-reported symptom remission.

Method: We re-examined data from Sequence Treatment Alternatives to Relieve Depression (STAR*D) study. Remission was measured using 50% reduction in Hamilton index. Pattern of antidepressant use was examined through five variables: (a) number of prior ineffective antidepressants, (b) duration of taking current antidepressant, (c) receiving therapeutic dose of the medication, and (d) switching to another medication, or (e) augmenting with another antidepressant. The likelihood ratio (LR) associated with each of these predictors was assessed in 90% of data (3329 cases) and evaluated in 10% of data (350 cases) set-aside for evaluation. The accuracy of predictions was calculated using Area under the Receiver Operating Curve (AROC).

Results: Patients who took antidepressants for 14 weeks (LR = 2.007) were more likely to have symptom remission. Prior use of 3 antidepressants reduced the odds of remission (LR = 0.771). Patients who received antidepressants below therapeutic dose were 5 times less likely to experience remission (LR = 0.204). Antidepressant that were augment or switched, almost never led to remission (LR = 0.008, LR = 0.002 respectively). Patterns of antidepressant use accurately (AROC = 0.93) predicted symptom remission.

Conclusion: Within the first 100 days, antidepressants use patterns could serve as a surrogate measure for patient-reported remission of symptoms.
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http://dx.doi.org/10.1186/s12888-021-03133-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931356PMC
March 2021

A surrogate measure for patient reported symptom remission in administrative data.

BMC Psychiatry 2021 03 4;21(1):121. Epub 2021 Mar 4.

Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.

Background: In real-world pragmatic administrative databases, patient reported remission is often missing.

Objective: We evaluate if, in administrative data, five features of antidepressant use patterns can replace patient-reported symptom remission.

Method: We re-examined data from Sequence Treatment Alternatives to Relieve Depression (STAR*D) study. Remission was measured using 50% reduction in Hamilton index. Pattern of antidepressant use was examined through five variables: (a) number of prior ineffective antidepressants, (b) duration of taking current antidepressant, (c) receiving therapeutic dose of the medication, and (d) switching to another medication, or (e) augmenting with another antidepressant. The likelihood ratio (LR) associated with each of these predictors was assessed in 90% of data (3329 cases) and evaluated in 10% of data (350 cases) set-aside for evaluation. The accuracy of predictions was calculated using Area under the Receiver Operating Curve (AROC).

Results: Patients who took antidepressants for 14 weeks (LR = 2.007) were more likely to have symptom remission. Prior use of 3 antidepressants reduced the odds of remission (LR = 0.771). Patients who received antidepressants below therapeutic dose were 5 times less likely to experience remission (LR = 0.204). Antidepressant that were augment or switched, almost never led to remission (LR = 0.008, LR = 0.002 respectively). Patterns of antidepressant use accurately (AROC = 0.93) predicted symptom remission.

Conclusion: Within the first 100 days, antidepressants use patterns could serve as a surrogate measure for patient-reported remission of symptoms.
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http://dx.doi.org/10.1186/s12888-021-03133-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931356PMC
March 2021

Perceived helpfulness of bipolar disorder treatment: Findings from the World Health Organization World Mental Health Surveys.

Bipolar Disord 2021 Feb 26. Epub 2021 Feb 26.

Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.

Objectives: To examine patterns and predictors of perceived treatment helpfulness for mania/hypomania and associated depression in the WHO World Mental Health Surveys.

Methods: Face-to-face interviews with community samples across 15 countries found n = 2,178 who received lifetime mania/hypomania treatment and n = 624 with lifetime mania/hypomania who received lifetime major depression treatment. These respondents were asked whether treatment was ever helpful and, if so, the number of professionals seen before receiving helpful treatment. Patterns and predictors of treatment helpfulness were examined separately for mania/hypomania and depression.

Results: 63.1% (mania/hypomania) and 65.1% (depression) of patients reported ever receiving helpful treatment. However, only 24.5-22.5% were helped by the first professional seen, which means that the others needed to persist in help seeking after initial unhelpful treatments in order to find helpful treatment. Projections find only 22.9% (mania/hypomania) and 43.3% (depression) would persist through a series of unhelpful treatments but that the proportion helped would increase substantially if persistence increased. Few patient-level significant predictors of helpful treatment emerged and none consistently either across the two components (i.e., provider-level helpfulness and persistence after earlier unhelpful treatment) or for both mania/hypomania and depression. Although prevalence of treatment was higher in high-income than low/middle-income countries, proportional helpfulness among treated cases was nearly identical in the two groups of countries.

Conclusions: Probability of patients with mania/hypomania and associated depression obtaining helpful treatment might increase substantially if persistence in help-seeking increased after initially unhelpful treatments, although this could require seeing numerous additional treatment providers. In addition to investigating reasons for initial treatments not being helpful, messages reinforcing the importance of persistence should be emphasized to patients.
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http://dx.doi.org/10.1111/bdi.13066DOI Listing
February 2021

Perceived helpfulness of bipolar disorder treatment: Findings from the World Health Organization World Mental Health Surveys.

Bipolar Disord 2021 Feb 26. Epub 2021 Feb 26.

Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.

Objectives: To examine patterns and predictors of perceived treatment helpfulness for mania/hypomania and associated depression in the WHO World Mental Health Surveys.

Methods: Face-to-face interviews with community samples across 15 countries found n = 2,178 who received lifetime mania/hypomania treatment and n = 624 with lifetime mania/hypomania who received lifetime major depression treatment. These respondents were asked whether treatment was ever helpful and, if so, the number of professionals seen before receiving helpful treatment. Patterns and predictors of treatment helpfulness were examined separately for mania/hypomania and depression.

Results: 63.1% (mania/hypomania) and 65.1% (depression) of patients reported ever receiving helpful treatment. However, only 24.5-22.5% were helped by the first professional seen, which means that the others needed to persist in help seeking after initial unhelpful treatments in order to find helpful treatment. Projections find only 22.9% (mania/hypomania) and 43.3% (depression) would persist through a series of unhelpful treatments but that the proportion helped would increase substantially if persistence increased. Few patient-level significant predictors of helpful treatment emerged and none consistently either across the two components (i.e., provider-level helpfulness and persistence after earlier unhelpful treatment) or for both mania/hypomania and depression. Although prevalence of treatment was higher in high-income than low/middle-income countries, proportional helpfulness among treated cases was nearly identical in the two groups of countries.

Conclusions: Probability of patients with mania/hypomania and associated depression obtaining helpful treatment might increase substantially if persistence in help-seeking increased after initially unhelpful treatments, although this could require seeing numerous additional treatment providers. In addition to investigating reasons for initial treatments not being helpful, messages reinforcing the importance of persistence should be emphasized to patients.
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http://dx.doi.org/10.1111/bdi.13066DOI Listing
February 2021

Targeting Mitochondrial Dysfunction for Bipolar Disorder.

Curr Top Behav Neurosci 2021 ;48:61-99

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.

People with bipolar disorder (BD) all too often have suboptimal long-term outcomes with existing treatment options. They experience relapsing episodes of depression and mania and also have interepisodic mood and anxiety symptoms. We need to have a better understanding of the pathophysiology of BD if we are to make progress in improving these outcomes. This chapter will focus on the critical role of mitochondria in human functioning, oxidative stress, and the biological mechanisms of mitochondria in BD. Additionally, this chapter will present the evidence that, at least for some people, BD is a product of mitochondrial dysregulation. We review the modulators of mitochondria, the connection between current BD medication treatments and mitochondria, and additional medications that have theoretical potential to treat BD.
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http://dx.doi.org/10.1007/7854_2020_152DOI Listing
March 2021

Association Between Care Utilization and Anxiety Outcomes in an On-Demand Mental Health System: Retrospective Observational Study.

JMIR Form Res 2021 Jan 26;5(1):e24662. Epub 2021 Jan 26.

Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, United States.

Background: Anxiety is an extremely prevalent condition, and yet, it has received notably less attention than depression and other mental health conditions from a research, clinical, and public health perspective. The COVID-19 pandemic has only exacerbated growing concerns about the burden of anxiety due to the confluence of physical health risks, economic stressors, social isolation, and general disruption of daily activities.

Objective: This study examines differences in anxiety outcomes by care modality (coaching, teletherapy and telepsychiatry, and combined care) within an on-demand mental health system. We also explore the association between levels of engagement within each care modality and odds of improvement in symptoms of anxiety.

Methods: We conducted a retrospective observational study of individuals who accessed Ginger, an on-demand mental health system. Data were collected from 1611 Ginger members between January 1, 2018, and December 31, 2019. We used logistic regression to assess the association between care modality and improvement in anxiety symptoms. Within each modality, we assessed the association between level of engagement and improvement.

Results: Of 1611 Ginger members, 761 (47.0%) experienced a decrease in anxiety symptoms, as measured by a change from a positive to a negative 2-item Generalized Anxiety Disorder (GAD-2) screen. Among members who still screened positive at follow-up (865/1611, 53%), a total of 192 members (11.9%) experienced a clinically significant score reduction in the full GAD-7 (ie, a score reduction of >5 points), even though their GAD-2 scores were still positive. All modalities showed increased odds of improvement compared to those who were not engaged with coaching or clinical services ("app-only"). Higher GAD-7 intake scores were also associated with decreased odds of improvement.

Conclusions: This study found increased odds of anxiety improvement for all care modalities compared to those who did not engage in care, with larger effect sizes for higher utilization within all care modalities. Additionally, there is a promising observation that those engaged in combined care (teletherapy and text-based coaching) had the greatest odds of anxiety improvement. Future directions include more detailed classifications of utilization patterns and an exploration of explanations and solutions for lower-utilization members.
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http://dx.doi.org/10.2196/24662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872836PMC
January 2021

Wrestling With Antidepressant Use in Bipolar Disorder: The Ongoing Debate.

J Clin Psychiatry 2021 01 19;82(1). Epub 2021 Jan 19.

Department of Psychiatry, NYU Langone Health, New York, New York, USA.

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http://dx.doi.org/10.4088/JCP.19ac13181DOI Listing
January 2021

Efficacy and safety of fecal microbiota transplantation for the treatment of diseases other than infection: a systematic review and meta-analysis.

Gut Microbes 2020 11;12(1):1-25

IMPACT, the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Deakin University , Geelong, Australia.

The intestinal microbiome has been identified as a key modifier for a variety of health conditions. Fecal Microbiota Transplantation (FMT) has emerged as a fast, safe, and effective means by which to modify the intestinal microbiome and potentially treat a variety of health conditions. Despite extensive research of FMT for CDI, there is a lack of clarity informed by systematic synthesis of data regarding the safety and efficacy of FMT for other health conditions. This systematic review used PRISMA guidelines and was prospectively registered with PROSPERO (CRD42018104243). In March 2020, a search of MEDLINE, EMBASE, and PsycINFO was conducted. We identified 26 eligible studies. A meta-analysis of FMT for active Ulcerative Colitis (UC) showed that FMT significantly improved rates of clinical remission (OR = 3.634, 95% CI = 1.940 to 6.808, I = 0%, < .001), clinical response (OR = 2.634, 95% CI = 1.441 to 4.815, I = 33%, = .002) and endoscopic remission (OR = 4.431, 95% CI = 1.901 to 10.324, I = 0%, = .001). With respect to Irritable Bowel Syndrome, a meta-analysis showed no significant change in symptoms following FMT ( = .739). Hepatic disorders, metabolic syndrome, and antibiotic-resistant organisms were conditions with emerging data on FMT. Serious adverse events (AE) were more often reported in control group participants (n = 43) compared with FMT group participants (n = 26). There were similar rates of mild to moderate AE in both groups. Preliminary data suggest that FMT is a potentially safe, well-tolerated and efficacious treatment for certain conditions other than CDI, with evidence for active UC being the most compelling.
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http://dx.doi.org/10.1080/19490976.2020.1854640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757860PMC
November 2020

Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation.

Prostaglandins Leukot Essent Fatty Acids 2021 01 5;164:102219. Epub 2020 Dec 5.

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA.

Background: Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients.

Methods: In a 2-site study, 61 MDD patients with body mass index >25 kg/m and serum high-sensitivity C-reactive protein ≥3 μg/mL were enrolled in a 12-week randomized trial comparing EPA 1, 2, and 4 g/d to placebo. Plasma EPA (mol%) and SPMs (pg/mL) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry.

Results: Plasma EPA and SPM concentrations did not change in the placebo group during 12 weeks of treatment. Plasma EPA and EPA-derived metabolites increased significantly and dose-dependently in all EPA supplementation arms. The increase in 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of RvE1-3, was significantly greater with the 4 g/d EPA dose than the other doses from week 4 to 12. RvE1 was undetected in all treatment groups, while RvE2 was detected in half of the subjects both at baseline and after treatment, with dose-dependent increases. RvE3 was detected only after supplementation, dose-dependently. A significant reduction in plasma arachidonic acid (AA), relative to baseline, was observed in all EPA arms. This was in contrast with an increase in AA-derived SPM lipoxin B4 (LXB4) in the 4 g/d arm.

Conclusions: Our results show a robust effect of EPA 4 g/d supplementation in increasing plasma EPA and 18-HEPE levels, associated with improved conversion to RvE2-3, and LXB4 levels.
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http://dx.doi.org/10.1016/j.plefa.2020.102219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855824PMC
January 2021

Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation.

Prostaglandins Leukot Essent Fatty Acids 2021 01 5;164:102219. Epub 2020 Dec 5.

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA.

Background: Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients.

Methods: In a 2-site study, 61 MDD patients with body mass index >25 kg/m and serum high-sensitivity C-reactive protein ≥3 μg/mL were enrolled in a 12-week randomized trial comparing EPA 1, 2, and 4 g/d to placebo. Plasma EPA (mol%) and SPMs (pg/mL) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry.

Results: Plasma EPA and SPM concentrations did not change in the placebo group during 12 weeks of treatment. Plasma EPA and EPA-derived metabolites increased significantly and dose-dependently in all EPA supplementation arms. The increase in 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of RvE1-3, was significantly greater with the 4 g/d EPA dose than the other doses from week 4 to 12. RvE1 was undetected in all treatment groups, while RvE2 was detected in half of the subjects both at baseline and after treatment, with dose-dependent increases. RvE3 was detected only after supplementation, dose-dependently. A significant reduction in plasma arachidonic acid (AA), relative to baseline, was observed in all EPA arms. This was in contrast with an increase in AA-derived SPM lipoxin B4 (LXB4) in the 4 g/d arm.

Conclusions: Our results show a robust effect of EPA 4 g/d supplementation in increasing plasma EPA and 18-HEPE levels, associated with improved conversion to RvE2-3, and LXB4 levels.
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http://dx.doi.org/10.1016/j.plefa.2020.102219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855824PMC
January 2021

How to Evaluate Patients for Tardive Dyskinesia.

J Clin Psychiatry 2020 12 1;82(1). Epub 2020 Dec 1.

Dauten Family Center for Bipolar Treatment Innovation, and the Depression Clinical and Research Program, Massachusetts General Hospital; and Department of Psychiatry, Harvard Medical School, Boston

​​​​​​​​ Tardive dyskinesia (TD) is a serious and potentially irreversible movement disorder that occurs in 20%-50% of patients taking antipsychotic drugs. TD is also associated with several other classes of medications, including antidepressants, antihistamines, decongestants, mood stabilizers, and stimulants. As more people are prescribed medications that can increase the risk for TD, it is important that clinicians learn how to systematically and reasonably evaluate their patients for this potentially dangerous and debilitating condition.
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http://dx.doi.org/10.4088/JCP.NU19047BR1CDOI Listing
December 2020

Clinical Correlates of False Positive Assignment in Bipolar Screening Measures Across Psychiatric Diagnoses among Patients without Bipolar Disorder.

Psychiatry Investig 2020 Nov 18;17(11):1118-1125. Epub 2020 Nov 18.

Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Objective: In this study, we aimed to determine clinical correlates of false positive assignment (FPA) on commonly used bipolar screening questionnaires.

Methods: A retrospective chart review was conducted to a total of 3885 psychiatric outpatients. After excluding patients who have bipolar spectrum illnesses, patients who were assigned as having hypomania on the mood disorder questionnaire (MDQ) or the hypomania checklist-32 (HCL-32) were identified as patients who had FPA. Psychiatric diagnoses and severity of emotional symptoms were compared between patients with and without FPA.

Results: Patients with FPA on the MDQ showed significant associations with presence of major depressive disorder, generalized anxiety disorder, and alcohol-use disorder, while patients with FPA on the HCL-32 showed associations with presence of panic disorder and agoraphobia. FPA on the MDQ was also associated with greater emotional symptoms and lifetime history of suicide attempts. Logistic regression analysis showed that male sex, younger age, presence of alcohol-use disorder, and severity of depression and obsessive-compulsive symptoms were significantly associated with FPA on the MDQ.

Conclusion: The FPA for the MDQ was associated with clinical factors linked to trait impulsivity, and the FPA for both the MDQ and the HCL-32 could be related to increased anxiety.
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http://dx.doi.org/10.30773/pi.2020.0246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711125PMC
November 2020

Collaborating With Patients to Make Treatment Decisions Based on Benefits and Risks of Medications Associated With Tardive Dyskinesia.

J Clin Psychiatry 2020 11 3;81(6). Epub 2020 Nov 3.

Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital; and Harvard Medical School, Boston

​​​​​​ Many patients who are at risk for tardive dyskinesia fear that they might develop the involuntary neurological movement disorder, yet it is possible for clinicians to convey a realistic assessment of the benefits and risks of medications that might induce TD. Clinicians need to be aware of the importance of communicating reasonable risk in a way that will not alarm patients, using tools such as probabilities and phronesis in discussions with their patients.
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http://dx.doi.org/10.4088/JCP.NU19047BR2CDOI Listing
November 2020

Assessment of Behavioral Health Services Use Among Low-Income Medicare Beneficiaries After Reductions in Coinsurance Fees.

JAMA Netw Open 2020 10 1;3(10):e2019854. Epub 2020 Oct 1.

Harvard Medical School, Boston, Massachusetts.

Importance: Medicare has historically imposed higher beneficiary coinsurance for behavioral health services than for medical and surgical care but gradually introduced parity between 2009 and 2014. Although Medicare insures many people with serious mental illness (SMI), there is limited information on the impact of coinsurance parity in this population.

Objective: To examine the association between coinsurance parity and outpatient behavioral health care use among low-income beneficiaries with SMI.

Design, Setting, And Participants: This cohort study used Medicare claims data for a 50% national sample of lower-income Medicare beneficiaries from January 1, 2007, to December 31, 2016. The study sample included patients with SMI (schizophrenia, bipolar disorder, or major depressive disorder). Data analysis was performed from August 1, 2018, to July 15, 2020.

Exposures: Reduction in behavioral health care coinsurance from 50% to 20% between January 1, 2009, and January 1, 2014.

Main Outcomes And Measures: Total annual spending for outpatient behavioral health care visits and the percentage of beneficiaries with an annual outpatient behavioral health care visit overall, with a prescriber, and with a psychiatrist. A difference-in-difference approach was used to compare outcomes before and after the reduction in coinsurance for beneficiaries with and without cost-sharing decreases. Linear regression models with beneficiary fixed effects that adjusted for time-changing beneficiary- and area-level covariates were used to examine changes in outcomes.

Results: The study included 793 275 beneficiaries with SMI in 2008; 518 893 (65.4%) were younger than 65 years (mean [SD] age, 57.6 [16.1] years), 511 265 (64.4%) were female, and 552 056 (69.6%) were White. In 2008, the adjusted percentage of beneficiaries with an outpatient behavioral health care visit was 40.7% (95% CI, 40.4%-41.0%) among those eligible for the cost-sharing reduction and 44.9% (95% CI, 44.9%-45.0%) among those with free care. The mean adjusted out-of-pocket costs for outpatient behavioral health care visits decreased from $132 (95% CI, $129-$136) in 2008 to $64 (95% CI, $61-$66) in 2016 among those with reductions in cost-sharing. The adjusted percentage of beneficiaries with behavioral health care visits increased to 42.2% (95% CI, 41.9%-42.5%) in the group with a reduction in coinsurance and to 47.2% (95% CI, 47.0%-47.3%) in the group with free care. The cost-sharing reduction was not positively associated with visits (eg, relative change of -0.76 percentage points [95% CI, -1.12 to -0.40 percentage points] in the percentage of beneficiaries with outpatient behavioral health care visits in 2016 vs 2008).

Conclusions And Relevance: This cohort study found that beneficiary costs for outpatient behavioral health care decreased between 2009 and 2014. There was no association between cost-sharing reductions and changes in behavioral health care visits. Low levels of use in this high-need population suggest the need for other policy efforts to address additional barriers to behavioral health care.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.19854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545309PMC
October 2020

Pre-diagnostic and post-diagnostic psychopharmacological treatment of 16 288 patients with bipolar disorder.

Bipolar Disord 2021 Jun 29;23(4):357-367. Epub 2020 Jul 29.

Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.

Objectives: The aim was to describe the pre-diagnostic and post-diagnostic psychopharmacological treatment of bipolar disorder over the past two decades.

Methods: We identified all 16 288 individuals aged ≥ 18 years, who received their first diagnosis of bipolar disorder at a psychiatric hospital in Denmark between 1997 and 2014. For each calendar year, we calculated the proportion of patients (with index date in the respective calendar years) who were prescribed psychopharmacological treatment in the 2 years preceding and the 2 years following the date of the first diagnosis of bipolar disorder. For patients diagnosed with bipolar disorder from 2007 to 2010 (n = 3949), we described the psychopharmacological treatment from 1995 to 2016, that is, from up to 16 years prior to and up to 10 years after the diagnosis.

Results: Concomitant use of ≥ 2 antidepressants in the 2 years preceding the bipolar disorder diagnosis increased over the study period. In the 2 years following the diagnosis, the use of lithium decreased, while use of atypical antipsychotics (particularly quetiapine), valproate, and lamotrigine increased over the study period. During the 10 years following the diagnosis, 53%-90% of the patients received any psychotropic drug while 12%-26% received treatment with an antidepressant without overlapping treatment with a mood-stabilizing drug.

Conclusion: The increased use of two or more antidepressants suggests more focus on bipolar disorder as a differential diagnosis to treatment-resistant unipolar depression. The decreased use of lithium (consistent with international trends) and the prevalent use of antidepressants without overlapping treatment with a drug with mood-stabilizing properties are concerning.
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http://dx.doi.org/10.1111/bdi.12976DOI Listing
June 2021

Adjunctive antidepressant treatment among 763 outpatients with bipolar disorder: Findings from the Bipolar CHOICE and LiTMUS trials.

Depress Anxiety 2021 02 29;38(2):114-123. Epub 2020 Jun 29.

Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.

Background: Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co-occurring manic symptoms affect treatment response.

Methods: Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N = 482) and Lithium Treatment Moderate-Dose Use Study (N = 281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline-based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts.

Results: Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co-occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales.

Conclusions: In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline-based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment-by-indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants.
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http://dx.doi.org/10.1002/da.23069DOI Listing
February 2021

A taxonomy of clinical response to mood stabilizers.

Bipolar Disord 2021 02 21;23(1):24-32. Epub 2020 Jun 21.

Université Paris Diderot and INSERM UMRS1144, Paris, France.

Introduction: Although clinical practice guidelines (CPG) identify first, second- and third-line mood stabilizer (MS) treatments, they rarely define clinical response to prophylaxis or the core issues to be considered. This project aimed to develop a template for describing how clinical response may be classified and a framework to assist decision-making and monitoring of response in day-to-day practice.

Method: A scoping exercise was undertaken followed by narrative synthesis of (a) qualitative and quantitative definitions of MS response applied in clinical and research practice and (b) potential confounders (eg, non-adherence; tolerability issues) of relevance to routine practice, for example, the concepts are applicable to individuals with bipolar disorder for whom sustained remission is a less realistic goal. Expert consensus was employed to develop a taxonomy of response and key concepts that inform clinical judgements about MS response.

Results: Five core constructs can be used to systematize clinical judgements regarding MS response and its monitoring: (a) quantitative, qualitative and/or patient-reported outcome measures (PROMS), (b) personalized assessment of the acceptable benefit-to-harm ratio of a proposed treatment, (c) adequacy of treatment exposure (dose, duration, therapeutic monitoring and adherence), (d) illness activity pre- and post-MS initiation, and (e) other potential confounders (co-prescription of MS; polypharmacy) or protective factors (eg, psychosocial factors).

Conclusions: This heuristic framework might be used as a teaching aid or by clinicians who wish to take a more systematic approach to developing shared criteria for judging MS response that better match patient expectations and preferences. Heuristic approaches also allow seamless introduction of new evidence.
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http://dx.doi.org/10.1111/bdi.12950DOI Listing
February 2021

Familial severe psychiatric history in bipolar disorder and correlation with disease severity and treatment response.

J Affect Disord 2020 08 16;273:131-137. Epub 2020 May 16.

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Background: Bipolar disorder is a heritable disorder, and we aimed to assess the impact of family history of mental disorders in first-degree relatives on the severity and course of bipolar disorder.

Methods: The Bipolar CHOICE (lithium versus quetiapine) and LiTMUS (optimized treatment with versus without lithium) comparative effectiveness studies were similar trials among bipolar disorder outpatients studying four different randomized treatment arms for 24 weeks. Patients self-reported on six severe mental disorders among first-degree relatives. We performed ANOVA and linear regression regarding disease severity measures, sociodemographic and cardiometabolic markers and mixed effects linear regression to evaluate treatment response.

Results: Among 757 patients, 644 (85.1%) reported at least one first-degree relative with a severe mental disorder (mean=2.8; standard deviation=2.2; range=0-13). Depression (67.1%), alcohol abuse (51.0%) and bipolar disorder (47.0%) were the most frequently reported disorders. Familial psychiatric history correlated with several disease severity measures (hospitalizations, suicide attempts, and earlier onset) and sociodemographic markers (lower education and household income) but not with cardiometabolic markers (e.g. cholesterol or waist circumference) or cardiovascular risk scores, e.g. the Framingham risk score. Patients with familial psychiatric history tended to require more psychopharmacological treatment (p=0.054) but responded similarly (all p>0.1) to all four treatment arms.

Conclusions: Our findings indicate that familial psychiatric history is common among outpatients with bipolar disorder and correlates with disease severity and sociodemographic measures. Patients with a greater familial psychiatric load required more intense treatment but achieved similar treatment responses compared to patients without familial psychiatric history.
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http://dx.doi.org/10.1016/j.jad.2020.03.157DOI Listing
August 2020

20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings.

Am J Psychiatry 2020 08 21;177(8):706-715. Epub 2020 Apr 21.

Department of Public Health Sciences, School of Medicine, University of Connecticut, Farmington (Rhee); Department of Psychiatry, School of Medicine, Yale University, New Haven, Conn. (Rhee, Wilkinson); Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York (Olfson); and Center for Bipolar Treatment Innovation, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Harvard University, Boston (Nierenberg).

Objective: Pharmacological options for treating bipolar disorder have increased over the past 20 years, with several second-generation antipsychotics receiving regulatory approval in the 1990s. The authors describe trends in use of pharmacological agents in the outpatient management of bipolar disorder.

Methods: Using nationally representative data from the 1997-2016 National Ambulatory Medical Care Surveys, the authors examined trends in the use of mood stabilizers, first- and second-generation antipsychotics, and antidepressants among psychiatrist visits for which bipolar disorder was listed among the primary diagnoses. A logistic regression model was used to identify statistically significant trends, with covariates including age, gender, race/ethnicity, and primary insurance.

Results: Antipsychotics were increasingly more commonly prescribed, increasing from 12.4% of outpatient visits for bipolar disorder in the 1997-2000 period to 51.4% in the 2013-2016 period (adjusted odds ratio=5.05, 95% CI=3.65-7.01). Use of mood stabilizers decreased from 62.3% of visits for bipolar disorder in the 1997-2000 period to 26.4% in the 2013-2016 period (adjusted odds ratio=0.18, 95% CI=0.13-0.27). Prescription of antidepressants occurred in 47.0% of visits for bipolar disorder in the 1997-2000 period and 57.5% in the 2013-2016 period. Prescription of an antidepressant without a mood stabilizer increased substantially, from 17.9% in the 1997-2000 period to 40.9% in the 2013-2016 period (adjusted odds ratio=2.88, 95% CI=2.06-4.03).

Conclusions: Substantial changes have occurred in the treatment of bipolar disorder over the past 20 years, with second-generation antipsychotics in large measure supplanting traditional mood stabilizers. Antidepressant prescriptions persisted despite a lack of evidence for their efficacy in bipolar disorder and concerns about increasing the risk of mania. Research is needed to compare the real-world effectiveness and tolerability of newer antipsychotics with those of traditional mood stabilizers.
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http://dx.doi.org/10.1176/appi.ajp.2020.19091000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577523PMC
August 2020

20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings.

Am J Psychiatry 2020 08 21;177(8):706-715. Epub 2020 Apr 21.

Department of Public Health Sciences, School of Medicine, University of Connecticut, Farmington (Rhee); Department of Psychiatry, School of Medicine, Yale University, New Haven, Conn. (Rhee, Wilkinson); Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York (Olfson); and Center for Bipolar Treatment Innovation, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Harvard University, Boston (Nierenberg).

Objective: Pharmacological options for treating bipolar disorder have increased over the past 20 years, with several second-generation antipsychotics receiving regulatory approval in the 1990s. The authors describe trends in use of pharmacological agents in the outpatient management of bipolar disorder.

Methods: Using nationally representative data from the 1997-2016 National Ambulatory Medical Care Surveys, the authors examined trends in the use of mood stabilizers, first- and second-generation antipsychotics, and antidepressants among psychiatrist visits for which bipolar disorder was listed among the primary diagnoses. A logistic regression model was used to identify statistically significant trends, with covariates including age, gender, race/ethnicity, and primary insurance.

Results: Antipsychotics were increasingly more commonly prescribed, increasing from 12.4% of outpatient visits for bipolar disorder in the 1997-2000 period to 51.4% in the 2013-2016 period (adjusted odds ratio=5.05, 95% CI=3.65-7.01). Use of mood stabilizers decreased from 62.3% of visits for bipolar disorder in the 1997-2000 period to 26.4% in the 2013-2016 period (adjusted odds ratio=0.18, 95% CI=0.13-0.27). Prescription of antidepressants occurred in 47.0% of visits for bipolar disorder in the 1997-2000 period and 57.5% in the 2013-2016 period. Prescription of an antidepressant without a mood stabilizer increased substantially, from 17.9% in the 1997-2000 period to 40.9% in the 2013-2016 period (adjusted odds ratio=2.88, 95% CI=2.06-4.03).

Conclusions: Substantial changes have occurred in the treatment of bipolar disorder over the past 20 years, with second-generation antipsychotics in large measure supplanting traditional mood stabilizers. Antidepressant prescriptions persisted despite a lack of evidence for their efficacy in bipolar disorder and concerns about increasing the risk of mania. Research is needed to compare the real-world effectiveness and tolerability of newer antipsychotics with those of traditional mood stabilizers.
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http://dx.doi.org/10.1176/appi.ajp.2020.19091000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577523PMC
August 2020

Clozapine and the Course of Bipolar Disorder in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

Can J Psychiatry 2020 04 21;65(4):245-252. Epub 2020 Jan 21.

Graduate Program in Psychiatry and Behavioral Sciences, Hospital de Clínicas de Porto Alegre, Centro de Pesquisa Clínica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

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http://dx.doi.org/10.1177/0706743719900460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385420PMC
April 2020
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