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The prescriber’s guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression
- Vincent Van den Eynde, Wegdan R. Abdelmoemin, Magid M. Abraham, Jay D. Amsterdam, Ian M. Anderson, Chittaranjan Andrade, Glen B. Baker, Aartjan T.F. Beekman, Michael Berk, Tom K. Birkenhäger, Barry B. Blackwell, Pierre Blier, Marc B.J. Blom, Alexander J. Bodkin, Carlo I. Cattaneo, Bezalel Dantz, Jonathan Davidson, Boadie W. Dunlop, Ryan F. Estévez, Shalom S. Feinberg, John P.M. Finberg, Laura J. Fochtmann, David Gotlib, Andrew Holt, Thomas R. Insel, Jens K. Larsen, Rajnish Mago, David B. Menkes, Jonathan M. Meyer, David J. Nutt, Gordon Parker, Mark D. Rego, Elliott Richelson, Henricus G. Ruhé, Jerónimo Sáiz-Ruiz, Stephen M. Stahl, Thomas Steele, Michael E. Thase, Sven Ulrich, Anton J.L.M. van Balkom, Eduard Vieta, Ian Whyte, Allan H. Young, Peter K. Gillman
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- Journal:
- CNS Spectrums / Volume 28 / Issue 4 / August 2023
- Published online by Cambridge University Press:
- 15 July 2022, pp. 427-440
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This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.
Safety of Using a Combinatorial Pharmacogenomic Test for Patients with Major Depressive Disorder in the GUIDED trial
- Sagar V. Parikh, Gabriela K. Khazanov, Michael E. Thase, Anthony J. Rothschild, Boadie W. Dunlop, Charles DeBattista, Charles R. Conway, Brent P. Forester, Richard C. Shelton, Matthew Macaluso, James Li, Kunbo Yu, Michael R. Jablonski, Stephanie Meek, John F. Greden
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, pp. 169-170
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Background
Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).
Materials and MethodsPatients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.
ResultsMost patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41–2.83) and RR 2.25 (95% CI 1.39–3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15–0.99, p=0.048). No other significant differences in risk were observed at week 8.
ConclusionThese data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.
FundingMyriad Neuroscience/Assurex Health
150 HAM-D6 Outcomes in a Randomized, Controlled Trial Evaluating the Utility of Combinatorial Pharmacogenomics in Depression
- Boadie W. Dunlop, Sagar V. Parikh, Maitrey Patel, Anthony J. Rothschild, Michael E. Thase, Charles DeBattista, Charles R. Conway, Brent P. Forester, Richard C. Shelton, Matthew Macaluso, James Li, Krystal Brown, Lisa Brown, Michael R. Jablonski, John F. Greden
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 295-296
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Background:
The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.
Methods:Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).
Results:At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).
Conclusions:Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.
Funding Acknowledgements:Assurex Health, Inc.
49 Combinatorial Pharmacogenomics to Guide Treatment Selection for Major Depressive Disorder: A Large, Blinded, Randomized Controlled Trial
- John F. Greden, Anthony J. Rosthschild, Michael Thase, Boadie W. Dunlop, DMH Charles DeBattista, Charles R. Conway, Brent P. Forester, Francis M. Mondimore, Richard C. Shelton, James Li, Alexa Gilbert, Lindsey Burns, Michael Jablonski, Bryan Dechairo, Sagar Parikh
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 202-203
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Background
Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
Methods1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
ResultsAt week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
ConclusionsCombinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
Suicidal ideation and other persisting symptoms after CBT or antidepressant medication treatment for major depressive disorder
- Boadie W. Dunlop, Philip E. Polychroniou, Jeffrey J. Rakofsky, Charles B. Nemeroff, W. Edward Craighead, Helen S. Mayberg
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- Journal:
- Psychological Medicine / Volume 49 / Issue 11 / August 2019
- Published online by Cambridge University Press:
- 12 September 2018, pp. 1869-1878
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Background
Persisting symptoms after treatment for major depressive disorder (MDD) contribute to ongoing impairment and relapse risk. Whether cognitive behavior therapy (CBT) or antidepressant medications result in different profiles of residual symptoms after treatment is largely unknown.
MethodsThree hundred fifteen adults with MDD randomized to treatment with either CBT or antidepressant medication in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study were analyzed for the frequency of residual symptoms using the Montgomery Asberg Depression Rating Scale (MADRS) item scores at the end of the 12-week treatment period. Separate comparisons were made for treatment responders and non-responders.
ResultsAmong treatment completers (n = 250) who responded to CBT or antidepressant medication, there were no significant differences in the persistence of residual MADRS symptoms. However, non-responders treated with medication were significantly less likely to endorse suicidal ideation (SI) at week 12 compared with those treated with CBT (non-responders to medication: 0/54, 0%, non-responders to CBT: 8/30, 26.7%; p = .001). Among patients who terminated the trial early (n = 65), residual MADRS item scores did not significantly differ between the CBT- and medication-treated groups.
ConclusionsDepressed adults who respond to CBT or antidepressant medication have similar residual symptom profiles. Antidepressant medications reduce SI, even among patients for whom the medication provides little overall benefit.
Will current socioeconomic trends produce a depressing future for men?
- Boadie W. Dunlop, Tanja Mletzko
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- The British Journal of Psychiatry / Volume 198 / Issue 3 / March 2011
- Published online by Cambridge University Press:
- 02 January 2018, pp. 167-168
- Print publication:
- March 2011
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The changing economic and social environment of Western nations is having a profound impact on men's lives. Men who assume a greater share of roles traditionally filled by women will experience challenges to traditional sources of male self-esteem, potentially heightening the risk for depressive disorders among men.
Conceptualizing Treatment Nonadherence in Patients with Bipolar Disorder and PTSD
- Jeffrey J. Rakofsky, Steven T. Levy, Boadie W. Dunlop
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- CNS Spectrums / Volume 16 / Issue 1 / January 2011
- Published online by Cambridge University Press:
- 01 January 2011, pp. 11-20
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Treatment nonadherence is a concern among patients with bipolar disorder and posttraumatic stress disorder (PTSD). PTSD is common among patients with bipolar disorder and those with this comorbidity often have a more severe course of illness. While many factors have been associated with nonadherence in bipolar disorder patients and in PTSD patients, almost no research has focused on the factors associated with non-adherence in bipolar disorder patients with comorbid PTSD. Studies in primary bipolar disorder samples reveal patient, illness, drug and clinician characteristics associated with nonadherence while studies in primary PTSD samples reveal a significantly shorter list of patient, illness and drug characteristics. Shared risk factors between these two populations and the characteristics that predict noncompliance in only one population but often present in the other, suggest a high likelihood of nonadherence in the bipolar disorder-PTSD population. For bipolar disorder-PTSD patients with early childhood trauma, noncompliance may be related to the trauma-related meanings attributed to interactions with their physicians and their prescribed medications. Given the high side effect burden of bipolar disorder treatments and the importance of lifelong adherence, clinicians should vigilantly monitor for nonadherence in their bipolar disorder-PTSD patients and be particularly aware of patient-physician psychodynamics that might contribute to this behavior.