Samantha A. Gnanasegaram, MD

Major depressive disorder (MDD) is the leading cause of global disease burden as measured in both years lived with disability as well as disability adjusted life-years.

 Aside from the human cost, there is significant economic burden incurred by sufferers as well as our health care system as a whole—a figure estimated to be $210.5 billion yearly.

 Although half of this is accounted for by work-related absenteeism and reduced productivity losses, the other half is attributed to direct medical costs involved in management and treatment which is shared by patients, employees, and our society.

MDD can be difficult to treat to remission, as it is not uncommon for inadequate response to first-line treatment modalities. As such, MDD often requires alternative approaches—one of which is augmentation with second-generation antipsychotics (SGA). Several SGA augmentation options exist and 3 are currently FDA approved (aripiprazole, quetiapine extended release, and brexpiprazole), while others have substantial evidence based on literature (cariprazine, lurasidone

). (Note that the olanzapine/fluoxetine combination is an entirely separate entity used for bipolar II; this article is only discussing augmentative agents). No clinical trial has compared the difference inefficacy of SGA augmentation, hence there is no guidance on which to use first.

In a value-based system where cost reduction is a major consideration, it is now more important than ever for physicians to optimize expenditure while preserving efficacy and outcomes. The authors of the study in this journal review

 evaluated the impact of SGA augmentation modalities on health care resource use and overall costs in real world practice. Unlike a previous similar observational study

, which compared adjunctive brexpiprazole with lurasidone and quetiapine in MDD and found no difference in such costs, this study has a longer follow-up time and greater sample size (uses more recent claims data from multiple large sources).

. What is the impact of the choice of adjunctive SGA on overall medical costs and health care utilization for MDD?

 Retrospective cohort analysis of de-identified administrative claims data from several large nationally representative claims databases.

The patients were gleaned from the following databases: MarketScan Commercial and Medicare Supplemental (inpatient, outpatient, and prescription drug claims of > 43.6 million employees, dependents, retirees in the United States with primary or Medicare supplemental coverage through privately insured fee for service, point of service, or capitated health plans); MarketScan Multi-State Medicaid (demographic and health care records of > 44 million Medicaid enrollees from multiple states); and Optum (claims and clinical data from various health care plans and providers for > 150 million). All were 18 years of age and older and identification was done based on the presence of at least 1 inpatient, or 2 outpatient claims for MDD based on ICD-9 and ICD-10 codes used between approximately 2014 and 2017. (See 

Patients were required to have had at least 1 prescription of aripiprazole, brexpiprazole, cariprazine, lurasidone and 150 mg to 300 mg augmentation dose range of quetiapine during this identification period with a mutually exclusive cohort for each medication. Participants were also required to be on an antidepressant during treatment for at least 30 days before augmentation. To ensure follow-up, data must have beenavailable for continued enrollment during treatment and 12 months following the index. Patientswith diagnoses of schizophrenia spectrum, bipolar disorder, Medicare/Medicaid dual eligible or capitated plans, were excluded.

Baseline variables related to illness severity were examined in the 1-year pre-index period. Patient demographics included age, gender, insurance, Charlson Comorbidity Index (CCI), number of Healthcare Cost and Utilization project, chronic conditions (both psychiatric and medical), medication use, and emergency department (ED) and hospital visits.

Primary outcome measures were psychiatric hospitalization and cost (total inpatient and outpatient service costs, distinct from pharmacy costs) during the follow-up period of 1 year. Secondary outcomesincluded psychiatry pharmacy costs (sum of claims for psychiatric medications in oral or long-acting injectable from pharmacy or outpatient setting) and medication adherence (proportion of days covered calculated as the number of available days of index therapy divided by 365 with adherence considered as ≥80%).

 Descriptive, unadjusted analyses were performed to assess differences among cohorts at baseline (χ2 tests for categorical variables, and 1-way analysis of variant Kruskal-Wallis test for continuous variables). To examine association among SGA augmentation and health outcomes, generalized linear models (GLM) with gamma distribution and log function were performed for psychiatric costs, given that the distribution of costs is right skewed. 

A 2-part model was conducted for psychiatric hospitalization costs with logistic regression for psychiatric hospitalizations, and GLM for hospitalization costs among hospitalized patients. All models were adjusted for age, gender, insurance type, CCI, MDD with psychosis, psychiatric and medical comorbidities, ED visits, hospitalizations, non-index antipsychotic use, other psychiatric medications. In the absence of a single acceptable measure of MDD severity available in administrative claims data, ED and hospital utilization as well as non-index antipsychotic use were used as proxy for severity. Costs were adjusted to 2017 US dollars using medical care component of the consumer price index.

 Almost 3 million patients with MDD were identified in the databases during the study period; of those patients, 1.8% started SGA augmentation during that time. After inclusion and exclusion criteria were applied, and cariprazine initiators were excluded because of the small sample size; 10,325 patients remained for the analysis (7657 aripiprazole, 1219 brexpiprazole, 827 lurasidone, and 622 quetiapine). Mean (SD) age was 48 (15.8), majority females (70.3%) and commercially insured (77%). Baseline characteristics differed among the adjunctive SGA cohorts—patients prescribed brexpiprazole were older but had lower ED visits and hospitalizations at baseline (p < 0.001 for all comparisons). Medication use at baseline was common and differed somewhat among the cohorts (p < 0.001 for all comparisons).

Unadjusted psychiatric costs (excluding pharmacy costs) during the follow-up period were lowest for brexpiprazole with mean (SD) of $3371 (10,708) followed by aripriprazole with $3871 (13,937), lurasidone with $6224 (20,656), and quetiapine with $10,670 (37,689). Patients taking brexpiprazole had the lowest mean (SD) hospitalization costs [$763 (6317)]. While brexpiprazole had the highest psychiatric pharmacy costs [$8961 (6104)], lurasidone had the highest total psychiatric costs [$14,196 (21,541)].

After controlling for baseline differences, the adjusted psychiatric costs (excluding pharmacy costs) differed significantly across the cohorts (p < 0.001). Compared with brexpiprazole, the psychiatric costs were significantly higher with lurasidone ($1662; p < 0.001) and quetiapine ($3894; p < 0.001), but did not differ between aripiprazole and brexpiprazole ($91; p = 0.563). The adjusted psychiatric pharmacy costs were significantly higher in the brexpiprazole group compared to the others.

Among hospitalized patients, the adjusted psychiatric hospitalization costs were $15,159 (p < 0.001) higher in quetiapine than in brexpiprazole cohorts. The odds of psychiatric hospitalization were also significantly higher with quetiapine than brexpiprazole [2.11 (1.46–3.04); p < 0.001]. No statistically significant differences were observed in risk of hospitalization comparing aripiprazole and lurasidone with brexpiprazole cohorts (p > 0.05). Across the spectrum, the lowest psychiatric hospitalization rates were found with brexpiprazole (4.3%, p < 0.001) while the highest rate was with quetiapine (8.6%, p < 0.001).

Adherence was low overall (percent of proportion of days covered >= 0.8 = 26.8%) and differed among the cohorts; quetiapine had the highest unadjusted medication adherence (29.6%), and the lurasidone group had the lowest (20.7%).

Based on a manufacturer-sponsored retrospective review of insurance claims filed between 2014 and 2017, adjunctive use of the SGAs brexpiprazole or aripiprazole in patients with MDD was associated with lower psychiatric costs compared with lurasidone and quetiapine augmentation. In comparison to quetiapine, brexpiprazole also was associated with a lower risk of psychiatric hospitalization, with no significant difference found between lurasidone, aripiprazole, and brexpiprazole. With no existing SGA augmentation guidelines and no evidence of efficacy between the different agents, these data on health care costs and utilization may be a consideration to clinicians in their decision-making process.

This large study based on the real world and with a 12-month follow up represents the latest and most comprehensive data regarding health care costs and utilization for patients with MDD who receive SGA augmentation. The authors believe the results are generalizable given the diverse sample of patients with a variety of insurance types. Earlier studies had limitations and did not compare brexpiprazole with aripiprazole. For example, a 2018 analysis conducted over a 6-month period found no differences in psychiatric costs between brexpiprazole, lurasidone, and quetiapine.

 Another analysis, based on clinical trial data with no head-to-head comparisons and follow-up found lower medical costs associated with brexpiprazole than quetiapine.

• The authors point out that the MDD diagnosis was identified from health insurance claims, which are designed for reimbursement purposes and can contain errors. Also, the design required antidepressant treatment before SGA augmentation; however, this does not indicate whether the patient had an adequate antidepressant trial not the type and class of antidepressant. Additionally, information such as symptom relief and any type of measures to assess improvement of depressive symptoms could not be measured. The burden of disease among the different cohorts is hence not accounted for.

• Although the patients were indeed diverse, it is unclear how this can be generalizable to patients without insurance, who have very different profiles especially from a social determinants of health standpoint. The authors intentionally excluded anyone younger than 18, and the resultant sample inadvertently had an abundance of female participants around 48 years of age, predominantly with commercial insurance. There were also disproportionate numbers of patients on each of the SGA augmentation (74.2% were on aripiprazole, 11.8% on brexpiprazole, 8% on lurasidonel and 6% on quetiapine), which could skew the analysis and, as such, interpretations. This low sample size was the reason cariprazine was not included in the analysis as a cohort; hence, no data is available for this emerging modality. The Charleston comorbidity index, which quantifies an individual’s burden of disease and corresponding 1-year mortality risk, was 1 for all cohorts (the higher the score is toward 6, the higher the mortality risk and resource use).

• Interestingly, a low adherence rate was reported, in line with one of the bigger clinical challenges we face daily. Although adherence varied somewhat between the different agents, the difference was not overly significant. Given that this dropout rate was quite high, the data may be skewed to favor those adherent to treatment.

• Lastly, there seems to be heavy financial support from industry (the makers of brexpiprazole specifically), and the authors do report additional affiliations.

Although these data represent very useful information on a population-based level, a head to head prospectiverandomized-controlled trial evaluating the efficacy of the various SGA augmentative agents is still needed to substantiate the cost differences reported here.

is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction Section Editor for

is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and attending psychiatrist at New Hampshire Hospital, Concord, NH. The authors report no conflicts of interest concerning the subject matter of this article.

1. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. 

2. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). 

3. Suppes T, Silva R, Cucchiaro J, et al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind, placebo-controlled study. 

4. Fava M, Durgam S, Earley W, et al. Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial. 

5. Durgam S, Earley W, Guo H, et al. Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder. 

6. Yan T, Greene M, Chang E, et al. Impact of Atypical Antipsychotics as Adjunctive Therapy on Psychiatric Cost and Utilization in Patients with Major Depressive Disorder. 

7. Broder MS, Greene M, Yan T, Chang E, Hartry A, Yermilov I. Medication adherence, health care utilization, and costs in patients with major depressive disorder initiating adjunctive atypical antipsychotic treatment. 

8. Sussman M, Yu J, Kamat SA, et al. Cost-effectiveness of brexpiprazole adjunctive treatment for major depressive disorder. 

Articles

The authors explore adjunctive treatments for MDD and their impact on overall medical costs and health care utilization.

Adjunctive Atypical Antipsychotics in Major Depressive Disorder: What’s the Impact?

Major depressive disorder (MDD) is a prevalent and 

 for which first-line standard antidepressant treatment modalities lead to 

 As psychiatrists, we are faced with tough decisions on how to proceed in managing non-response in the remaining two-thirds. Strategies include antidepressant switching or augmentation with various agents. To complicate matters, a highly 

 for those with MDD is posttraumatic stress disorder (PTSD) with national surveys showing a 0.5 correlation.

 severity and very different challenges in terms of management compared with MDD alone.

 tackled a timely question: Should a PTSD comorbidity affect our decision of how to manage MDD non-response to a first line antidepressant treatment?

Should a concurrent PTSD diagnosis affect whether to augment or switch medications when MDD has not responded to a prior antidepressant trial?

 Secondary analysis of a randomized, single-blind, parallel-assignment trial (ClinicalTrials.gov identifier: NCT01421342).

 that generated the data based on which the 2020 secondary analysis

Participants included1522 Veterans Health Administration (VA) patients from 35 study sites who experienced suboptimal response to at least 1 course of selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor/mirtaza-pine antidepressant treatment meeting minimal standards for dose and duration.

 Patients were primarily men (85.2%) with a mean age of 54.4. A total of 717 participants (47.1%) had a co-occurring PTSD diagnosis. Patients all had a diagnosis of non-psychotic MDD and were referred by their VA clinicians.

Study assignment was random (1:1:1) to 3 treatment strategies: switch to bupropion (switch-BUP); augment current antidepressant with bupropion (aug-BUP); or augment current antidepressant with aripiprazole (aug-ARI).

Between December 2012 to May 2015, participants underwent 12 weeks of treatment with either switch-BUP (n = 511), aug-BUP (n = 506), or aug-ARI (n = 505). Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) determined remission (less than or equal to a score of 5) and response (reduction in score from baseline by 50% or more) by 12 weeks and relapse after remission (score of 11 or more for those who previously achieved remission). Long-term follow up lasted up to 24 weeks. Survival analyses compared treatment effects in patients with concurrent PTSD and those without it.

Remission and response outcomes for patients with and without comorbid PTSD were compared using Cox regression modelswith comorbid PTSD and treatment as independent variables with an interaction term for treatment and PTSD. Multivariable Cox regression models were developed using stepwise regression in which significant predictors of outcome that were associated with PTSD were added to the models to adjust estimates of PTSD and treatment effects for covariates. Comparisons were expressed by relative risk ratios (RR) estimated from hazard ratios from Cox models and 95% confidence intervals (CI), reporting the Wald test P values.

, 1137 of the 1522 randomized veterans (74.7%) completed the treatment phase. Remission rates at 12 weeks (primary outcome) were only 30% for all groups, with the highest scores from the aug-ARI group (

). Similarly, response (secondary outcome) was greatest for the aug-ARI group (74.3%). Anxiety was more frequent in the 2 bupropion groups. Adverse effects were more frequent in the aug-ARI group and included somnolence, akathisia, and weight gain.

Comparing the impact of a PTSD comorbidity

A greater proportion of African American and Hispanic patients were found in the comorbid PTSD group. Overall, patients with comorbid PTSD had more severe depressive symptoms on the QIDS as well as global clinical severity indexes and lower quality of life scores.

In terms of retention, 27.6% of the 717 participants with PTSD withdrew from the study before the 12 week completion compared to 23.2% of those without PTSD. The difference in dropout rates for those with PTSD versus those without PTSD was greatest in the aug-BUP group (29.5% versus 21.4%, respectively) but similar in the switch-BUP and aug-ARI groups.

In terms of remission, at 12 weeks there was a 43% lower risk of remissionfor those with comorbid PTSD (RR = 0.567; 95% CI, 0.462–0.697) with all 3 treatments, irrespective of the severity of MDD. Kaplan-Meier plots of cumulative probability of remission for each treatment group by PTSD status show remission rates are lower in the PTSD group; the switch-BUP treatment group had the lowest rate of remission.

Relative risk of response was also significant for those with PTSD (RR = 0.745; 95% CI, 0.658–0.843) and for each of the 3 treatments, reflecting a 25% lower symptom improvement among those with PTSD. For relapse after remission, the risk was not significantly greater among those with PTSD. The results across treatment groups were mixed, with significantly greater likelihood of relapse among participants with PTSD in the aug-BUP group but not among those in the switch-BUP or aug-ARI groups.

Comparing the impact of various treatment interventions

A comparison of the magnitude of treatment effects between pairs of treatments (risk ratios reflecting comparative effectiveness of paired treatments) among patients with and without 

 showed no significant differences in comparative treatment effectiveness on remission between patients with and without PTSD. In the analysis of response, augmentation with aripiprazole was associated with significantly greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (HR = 1.26; 95% CI, 1.01–1.59) and also in patients without PTSD (HR = 1.29; 95% CI, 1.05–1.57) (78.9% response with augment with aripiprazole versus 66.9% response with switching to bupropion).

There were no significant differences in response between augmentation with aripiprazole and augmentation with bupropion in either patients with PTSD or patients without PTSD. The analysis of relapse showed no significant differences between pairs of treatment groups with or without PTSD and minor interaction of treatment group and PTSD diagnosis (P = .15).

, with nonpsychotic moderate to severe MDD that was unresponsive to antidepressant treatment, those with comorbid PTSD showed greater disease burden at baseline and significantly lower remission and response with 3 next-step 12-week treatments.

 Augmentation with aripiprazole resulted in a small, yet statistically significant, increase in response likelihood at 12 weeks when compared with switching to bupropion irrespective of a comorbid PTSD diagnosis.

There were several limitations of the 2020 study. First, it was conducted within the VA system with a predominantly older male population with likely combat-related trauma histories. It is thus unclear whether results would generalize to the broader population with other underlying PTSD forms.

Second, despite inclusion of a greater proportion of participants with non-psychotic psychiatric comorbidities, there were still a number of exclusion criteria, including active substance use, which represents a significant comorbidity found in patients with MDD.

Third, all individuals included experienced a moderate degree of depression severity; hence, these findings cannot be extrapolated in the care of patients with mild and severe MDD.

Fourth, 26% of participants did not complete the study, resulting in a substantial dropout rate. It is also possible that the group that switched to bupropion may have experienced withdrawal from previous treatment, putting them at a disadvantage for dropout or other adverse outcomes.

Fifth, only 1 antidepressant and 1 antipsychotic were evaluated. Generality to other agents is unknown, especially to factors such as behavioral interventions, tricyclic antidepressants, monoamine oxidase inhibitors, electroconvulsive therapy, transcranial magnetic stimulation, and lithium augmentation.

Lastly, although there was no financial support from industry, authors disclosed some pharmaceutical affiliations, which may potentially lead to biases.

is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction section editor for

 is instructor in psychiatry at Dartmouth’s Geisel School of Medicine and Attending Psychiatrist at New Hampshire Hospital, Concord, NH. The authors report no conflicts of interest concerning the subject matter of this article.

GBD 2010: understanding disease, injury, and risk

2. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. 

Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice

3. Kessler RC, Berglund P, Demler O, et al. 

Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication

4. Post LM, Zoellner LA, Youngstrom E, Feeny NC. Understanding the relationship between co-occurring PTSD and MDD: symptom severity and affect. 

5. Mohamed S, Johnson GR, Chen P, et al. 

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial

. 2017;318(2):132–145. https://pubmed.ncbi.nlm.nih.gov/28697253/

6. Mohamed S, Johnson GR, Sevilimedu V, et al. 

Impact of concurrent posttraumatic stress disorder on outcomes of antipsychotic augmentation for major depressive disorder with a prior failed treatment: VAST-D randomized clinical trial

2020;81(4):19m13038. https://pubmed.ncbi.nlm.nih.gov/32603560/

This article was originally posted on August 5, 2020 under the title "Then and Now: Addressing Comorbid PTSD and MDD," and has since been updated. -Ed

The authors examine recent literature in order to assist psychiatrists in evaluating the findings and determining how to best put research findings into real-world practice.

Then and Now: Addressing Comorbid PTSD and MDD

Several years ago, I was approached by a pharmaceutical representative who wanted to tell me about a “new” agent, brexpiprazole. Sure, I was familiar with it having learned about it in training-the serotonin 1A and dopamine D2 receptors partial agonist and serotonin 2A and noradrenaline alpha receptors antagonist that was FDA-approved for schizophrenia and as adjunctive therapy to antidepressant for major depressive disorder (MDD).

 But there is no way I would use it; after all it was likely just another "pharma" push of a drug that would not work, right?

At least in academia we have been groomed to see such advancements as an advertisement or a marketing scheme, and it is taboo to engage in discussions, let alone prescribe, a marketed drug. Looking back now, it is way too often that we take on a narrow view and regard pharmaceutical companies as enemies rather than allies in providing the best treatments for our patients.

We have all had patients with refractory or partially responsive MDD, despite antidepressant treatment, patients who continue to suffer and have their lives turned upside down. According to the STAR*D study, only 30% achieve a level of symptom resolution that would be considered close to remission range.

 Augmentation with atypical antipsychotics, among other agents, has been proven to be effective. However, the adverse effect profiles are often intolerable, particularly from a sedation and metabolic standpoint.

After that sales representative visited, I happened to encounter a patient presenting to me as a new evaluation for a second opinion.

A woman in her mid to late 20s reported a multitude of neurovegetative depressive symptoms and complaints of anxiety. She was quite tearful and described feeling hopeless and nothing would help her feel “normal” again. She discussed having had a series of medication trials including most SSRIs, and SNRIs which either did not work or produced undesirable effects.

The patient even tried augmentation with lithium and other second-generation antipsychotics, the latter which were fairly intolerable due to either activation, sedation, or development of compulsions and various worries. Despite asking for help, she was rather hesitant to be thought of as a “guinea pig.”

Brexpiprazole was fresh in my mind at the time. It differs from other antipsychotics in its pharmacological profile. I presented her with several options, including brexpiprazole, in an attempt to empower her in her care, discussing the modes of actions, potential benefits, the risks. She agreed on a trial of the drug in addition to the antidepressant she was currently taking. At two-week follow-up, she reported feeling more at ease, now being able to not feel on edge during the day, having less irritability in her work and home life, and no longer becoming tearful in public.

She continued to experience an improvement in her mood at the next follow-up. She felt she had more energy and motivation to engage in activities she enjoyed, and she even started enjoying social interactions with friends and family.

Brexiprazole (Rexulti) has been on the market since 2015, hence it is relatively new. In recent years, meta-analyses of studies have attempted to generate post-marketing data and, indeed found evidence of efficacy as an adjunct in those with MDD with a relatively safe adverse effect profile.

 examined four phase-3 studies in adult patients with MDD who had inadequate response to antidepressants in which brexpiprazole was used. Here they pooled analysis of data from these six week-long randomized double-blind placebo controlled treatment phases of four studies, encompassing a total of 1853 patients using brexpiprazole (1 mg to 3 mg daily).

They evaluated efficacy using the Montgomery-Asberg Depression Rating Scale (MADRS) and safety by treatment-emergent adverse effects (TEAEs). From baseline to week six, treatment with antidepressant plus brexpiprazole 2 mg to 3mg per day showed significantly improved MADRS scores compared with antidepressant plus placebo. In terms of TEAEs, in the treatment arm several were identified such as akathisia (8 versus 2.6% for placebo); headache (5.8 versus 6% for placebo); and weight gain (5.8 versus 1.6% for placebo).

It is important to keep an open mind and be able to craft personalized treatment regimens for patients with depression. In medicine, one size does not fit all. We need to be familiar with all agents currently available to us and be able to implement such treatment modalities to best help patients who are suffering.

The above case is presented for instructional purposes only and does not represent any one individual. -Ed

is Assistant Professor of Psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH.

is Instructor in Psychiatry at Dartmouth’s Geisel School of Medicine and Attending Psychiatrist at New Hampshire Hospital, Concord, NH.

The authors report no conflicts of interest concerning the subject matter of this article.

1. Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: 

 characterization of a novel serotonin–dopamine activity modulator. 

2. Sinyor M, Schaffer A, Levitt A. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: A Review. 

3. Spielmans GI, Berman MI, Linardatos E, et al. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. 

4. Antoun Reyad A, Girgis E, Mishriky R. Efficacy and safety of brexpiprazole in acute management of psychiatric disorders: a meta-analysis of randomized controlled trials. 

https://www.ncbi.nlm.nih.gov/pubmed/32141908

5. Thase ME, Youakim JM, Skuban A, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a Phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. 

https://www.tandfonline.com/doi/full/10.1080/14656566.2019.1638913

A patient with refractory MDD continued to suffer and feel as though her life was turned upside down, despite treatment. Learn the outcome of the case.

Augmentation Strategies for Depression

Based on the currently available data, those over the age of 65, and of all ages with underlying medical comorbidities, are considered to be at higher risk for severe illness from coronavirus.

This is a new challenge all across medicine, and most institutions do not have set policies as of yet, so we can always learn from each other and learn from the institutions that have taken the lead. Remember that many of the people making the policies for our organizations are not medically trained, so don't be afraid to share your knowledge to keep yourself and others in your situation safe.

In this video, Samantha Gnanasegaram, MD, a psychiatrist New Hampshire Hospital, Concord, NH, talks about the challengers of being a clinician in the days of the coronavirus pandemic.

Videos

5 Tips to Protect Yourself During the Coronavirus Pandemic

This activity offers CE credits for:
	1. Physicians (CME)
	2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to provide a comprehensive understanding of the opioid-like effects of loperamide and kratom and raise awareness of potential dangers associated with use.

At the end of this CE activity, participants should be able to:

• Explain the evolutionary paths of loperamide and kratom

• Discuss the mechanisms for the opioid-like effects of loperamide and kratom

• Identify the pharmacodynamic/toxicodynamic effects of loperamide and kratom

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

 This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 

. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants:

 AANPCP and AAPA accept certificates of participation for educational activities certified for 

It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Cornel N. Stanciu, MD, MRO, has no disclosures to report.

Samantha A. Gnanasegaram, MD, has no disclosures to report.

Thomas M. Penders, MS, MD, has no disclosures to report.

Saeed Ahmed, MD (peer/content reviewer), has no disclosures to report.

 staff and CME Outfitters staff have no disclosures to report.

Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

For content-related questions email us at 

; for questions concerning CME credit call us at 

Of Americans 12 and older, 2 million have a substance use disorder (SUD) that involves prescription pain relievers and 591,000 have a SUD involving heroin.

 Withdrawal from opioids is extremely unpleasant and individuals often return to substance use to ameliorate symptoms. The individual may be interested in stopping opioid use altogether but has no access to FDA-approved treatment or wishes to pursue a more “natural” alternative.

In recent years, two agents have gained popularity as off-label opioid alternatives-loperamide and kratom. These are readily available at low costs and for these reasons they have at times been referred to as “the poor man’s methadone” and “poor man’s buprenorphine,” respectively. On drug-use websites and online forums, high doses of these agents have been promoted as options for opioid withdrawal management and, less often, for psychoactive effects.

Loperamide has been approved by the FDA for medical use since 1976. It is part of the World Health Organization’s List of Essential Medicine and is widely available as an inexpensive and over-the-counter (OTC) remedy used in managing diarrhea. Loperamide is marketed OTC under the brand name Imodium A-D but is also available as store brands and generic versions. As a piperidine opioid in nature, it was once a schedule V drug. At therapeutic doses, its actions are restricted to the gastrointestinal tissue by poor absorption and active efflux from the CNS by membrane transporter P-glycoprotein. The maximum daily dose is 8 mg for adults as OTC use and 16 mg by prescription.

When larger than recommended doses are taken, CNS penetration occurs. This practice of ingestion of large doses (in excess of 70 mg daily) has been gaining popularity among users of opioids to manage withdrawal symptoms and, less frequently, to achieve psychoactive opioid-like effects.

Early studies showed no abuse potential for loperamide; however, by 2013, reports of recreational use of 70 to 100 mg doses started surfacing.

 Subsequently, from 2011 to 2014 a 71% increase in loperamide-related presentations was noted by poison control agencies. In recent years, reports of extremely high doses have emerged.

 Users report using primarily to ease withdrawal symptoms but also, less often, as a substitute for opioids.

 Most users have a history of opioid use with no reports of loperamide as an initial, gateway drug.

 Unfortunately, national surveys do not track use, and the Drug Abuse Warning Network (DAWN) does not monitor loperamide use.

A dose-dependent effect is seen with loperamide that determines the anatomical system it acts on. Within the recommended dose of up to 16 mg daily, Î¼-opioid receptors are agonized at the large intestinal myenteric and submucosal plexi, stimulating secretion of inhibitory neurotransmitters to increase non-propulsive contractions thereby decreasing peristalsis and allowing for fluid and electrolyte absorption. CNS effects are avoided as transporter P-glycoprotein actively pumps it out at the blood brain barrier.

Above recommended doses, P-glycoprotein systems become saturated, and CNS entry occurs. Several agents (including loperamide) such as antineoplastic drugs, steroids, ketoconazole, and quinidine, can block the P-glycoprotein system, facilitating CNS entry. (Some users may supplement with these.) CYP 3A4 inhibitors allow loperamide to circumvent first pass effect.

Loperamide’s onset of action is 1-hour post-ingestion and reaches peak plasma levels between 3 to 5 hours, with a half-life between 7 to 19 hours. Users typically have to dose every 8 to 12 hours; however, sustained benefit of up to 2 days has also been reported by some. Doses range from 70 to 400 mg daily. Although use is with the intent of amelioration of withdrawal, in this range there is also potential for euphoric effects that tend to not be as pleasurable as with opioids.

 CNS effects do not include any analgesic benefits.

There have been several reports of the development of tolerance after weeks to months of use, resulting in the need to increase the dose by 25% to 50% increments.

 Withdrawal symptoms are also mentioned, which are similar to opioid withdrawal but milder and less prolonged. Most users report successfully being able to taper with limited symptoms.

 Unlike buprenorphine or methadone tapers, once loperamide is discontinued, cravings for opiates subside.

At therapeutic doses, there may be constipation, dizziness, nausea, and abdominal cramps. More serious yet rare adverse effects of long-term use include toxic megacolon, paralytic ileus, angioedema, and Stevens-Johnsons Syndrome.

 When administered in supra-therapeutic doses, cardiac life-threatening adverse effects include QTc prolongation, QRS widening, ventricular dysrhythmias, syncope, and sudden deaths.

 The FDA has responded by adding a warning to the drug label in 2016 and also has been working with manufacturers to limit the number of doses per package of OTC medication.

Routine drug screens do not pick up loperamide use; hence, a high degree of suspicion is required to detect abuse. Opioid users often present with respiratory depression, whereas those using supra-therapeutic loperamide doses will present with arrhythmias (ie, long QT, wide QRS) and may be awake and alert. Patients typically have histories of opioid use with recent discontinuation and will present with unexplained syncope and the electrocardiogram abnormalities. Identification of misuse should open discussion regarding the underlying reason for use, promoting treatment.

, is a deciduous tree related to the coffee family indigenous to Southeast Asia. Historically, its leaves were chewed or brewed as a tea (less commonly smoked) to help cope with the physical demands of laborers by improving endurance and reducing fatigue. In traditional medicine, kratom has also been used as an opium substitute. When used in small amounts (< 5 g), stimulant properties emerge such as increased alertness and stamina; however, in larger doses (>5 g) opioid-like sedative, euphoric, and anti-nociceptive properties are seen. Kratom leaves contain at least 40 identified alkaloids and various other organic molecules. The active constituents are mitragyine and 7-hydroxymitragynine; each leaf contains varied concentrations and proportions.

In recent years, because of its unique properties and “harmless” perception, kratom has been gaining popularity in parts of the Western world. It is available in headshops, health stores, and is sometimes grown locally or available over the Internet. Products are available as crushed or powdered leaves; sometimes as extracts or combined with other agents in tinctures or capsules for very low costs.

Although commercially available products show a recommended dose, the amount of actual active ingredient present is not certain. Kratom was legal to grow and purchase in all 50 states until 2015 when the Drug Enforcement Administration identified kratom as a substance of concern. As of June 2018, kratom is illegal to buy, sell, and use in Wisconsin, Rhode Island, Vermont, Indiana, Arkansas, Alabama, Washington, DC, as well as in some specific counties. Outside of the US, use and sale of kratom is illegal in Thailand and has been banned in Australia, Poland, Denmark, Sweden, Malaysia, and Vietnam.

A recent survey suggested that kratom was one of the most widely sold “legal highs,” offered in 44% of online shops. The 

National Survey of Drug Use and Monitoring the Future

 survey do not track kratom use and few data exist on the prevalence of kratom use. It is estimated by advocacy organizations that between 3 and 5 million Americans are regular users.

An anonymous online survey of 10,000 current users located through the American Kratom Association and search of social media in October 2016 had 8094 responses.

The majority of users were male (57%), nonhispanic white (82%), aged between 21 and 50 years; 40% disclosed their use to their medical provider; 55% were married; 57% were fully employed; and 82% had a college education. The most common use was as a dissolved powder (49%) taken with a beverage; 37% used capsules, and 13% used kratom as a prepared tea. The primary reason for use was self-treatment of chronic pain. A similar percentage reported using to relieve depressed or anxious mood. Adverse effects were reported by only 51 users.

It is estimated that 55% of regular users become dependent on kratom.

 Between 2011 and 2017 the number of calls to Poison Control Centers related to kratom exposures increased from one a month to two daily.

Isolation and chemical characterization of its components has been of interest since the 1960s with over 40 different alkaloids having been isolated to date, only two of which are active (mitragynine, 7-hydroxymitragynine). The composition of the plant varies significantly depending on the environment in which it is grown, breeding and harvesting techniques, and age of the plant. For example, a plant from Thailand has on average 66% mitragynine alkaloid content whereas one from Malaysia has approximately 12%; younger plants tend to have greater mitragynine content. The various different alkaloids found in the plant have unique properties: anti-nociceptive, anti-inflammatory, anti-depressant, or muscle relaxant.

Its two active constituents display opioid-like properties in vivo and in vitro. The potency at the opioid receptor has been found to exceed that of morphine. Competitive binding studies further examined affinity at the various opioid receptor subtypes and found a preference for the Îº receptors (antagonism) followed by Î¼ (partial agonism) and lastly Î´, which is a similar profile to buprenorphine.

 The highest potency of 7-hydroxymitragynine is at the Î¼ receptor.

 Mitragynine also plays a role in noradrenergic and serotonergic pathways where it stimulates postsynaptic Î±2 adrenergic receptors and inhibits 5-H2A receptors.

These properties explain how kratom counteracts withdrawal in opioid dependent individuals.

Mitragynine has a relatively short half-life as well as a large volume of distribution. Individuals using it to counteract opioid withdrawal require dosing as frequent as every 6 to 12 hours with withdrawal symptoms emerging 12 hours after last use and lasting up to 4 days.

When it comes to interactions of its multiple constituents with the CYP 450 system, one study found kratom may inhibit 2C9, 2D6, 3A4 isoenzymes and to some extent 1A2.

 This raises concern over the impact kratom use can have on clinical populations prescribed pharmacological agents.

Case reports document effects such as weight loss, insomnia, constipation and dehydration, skin hyperpigmentation, and fatigue occurring in chronic use of kratom.

 Some acute effects include seizures, delusions and hallucinations, respiratory depression, hepatotoxicity, coma, and death. In recent years emergency departments as well as poison call centers across the country have seen an increasing number of presentations related to kratom use. According to the State Unintentional Drug Overdose Reporting System, between July 2016 and June 2017, in 8 of the states reporting to the system a total of 25 deaths involved kratom co-ingestion.

 This number could be an underestimate since kratom testing and assessment for it is not uniform.

In one published report, a male patient addicted to hydromorphone attempted to use kratom to prevent withdrawal. He was admitted to the hospital after mixing kratom and modafinil and sustaining a generalized tonic-clonic seizure. It was deemed unclear whether the seizure resulted from the kratom or the drug combination.

Most reported cases involve mixing kratom with other agents or ingesting contaminated kratom products (eg, Krypton). In a case series from Sweden, researchers reported 9 cases of Krypton intoxication and death. The product known as “Krypton” is an herbal preparation of dried, crushed kratom leaves mixed primarily with another Î¼-opioid receptor agonist, O-desmethyltramadol which is known to cause seizures.

Abrupt discontinuation of high dose, long-term use of kratom mimics opioid withdrawal: chills, body aches, loose bowels, insomnia, restlessness and irritability, fatigue, anxiety and mood disturbances, among others. Symptoms begin 12 hours from last use and can last upwards of 4 days. Symptoms are positively correlated to the amount and duration of use; they are uncomfortable both physiologically and psychologically, which prompts return to use. Cravings are also present. In managing withdrawal, the best approach involves symptomatic management of a hyperadrenergic state. Use of regulated agents such as methadone and buprenorphine has been hindered from a medico-legal perspective and very few reports exist.

Kratom use during pregnancy can lead to neonatal abstinence syndrome in the neonate. Nothing is known about the extent of placental crossing of kratom’s active alkaloids. In two case reports, symptoms such as jitteriness, irritability, feeding intolerance, and vomiting emerged around day 2 postpartum requiring neonatal intensive care unit admission and standard opioid protocol with intravenous morphine subsequently tapered with oral formulation over 5 days.

Screening for kratom has its challenges. Since it is not detected through the standard urine toxicology screen, special confirmatory testing is necessary. Detection of breakdown products of mitragynine can be detected through gas chromatography coupled with mass spectrometry, liquid chromatography with linear ion trap mass spectrometry, or through electrospray tandem mass spectrometry.

Loperamide and kratom are growing in popularity because of their opioid-like effects. Motives include opioid withdrawal suppression or to taper off opioids as well as, less frequently, psychoactive effects. With loperamide, this practice requires above label doses, placing users at risk for cardiotoxicity among other effects. Kratom is concerning because of its variability in alkaloid composition and preparations that contain dangerous additives, as well as its potential for dependence and withdrawal on discontinuation. Clinicians need to be aware of such substitutional behaviors in those with a history of opioid use to provide proper diagnosis, management, and patient education.

Post-tests, credit request forms, and activity evaluations must be completed online at 

 (requires free account activation), and participants can print their certificate or statement of credit immediately (80% pass rate required). This Web site supports all browsers except Internet Explorer for Mac. For complete technical requirements and privacy policy, visit 

PLEASE NOTE THAT THE POST-TEST IS AVAILABLE ONLINE ONLY ON THE 20TH OF THE MONTH OF ACTIVITY ISSUE AND FOR 18 MONTHS AFTER.

Genetics in the Clinical Setting: The Role of Psychiatric Genetic Counseling