Differences in Response to Antidepressants in Combination with Mood Stabilizers and Antipsychotics for Unipolar and Bipolar Depression
A study published in the Journal of Clinical Psychopharmacology is the first to explore clinical response rates to antidepressants in combination augmentation strategies with either antipsychotics or mood stabilizers and to illuminate the differences between response to similar pharmacotherapies in patients with unipolar and bipolar depression. Antidepressant prescriptions in bipolar disorder have surged in the past two decades, from 17.9% to 40.9% of patients, mostly based on the success of newer antidepressants in treating unipolar depression. They remain the leading treatment prescribed for bipolar disorder, despite inconsistent evidence for efficacy and the occurrence of adverse events, such as treatment-emergent affective switch (TEAS).
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The study relied on data from a research database for patients followed at the McGill University Health Center’s Mood Disorders Clinic for 2 or more years (mean, 7.5 years). It included 206 patients; 76 met the criteria for treatment-resistant depression (TRD), failing two or more trials with different antidepressants in either monotherapy or combination therapy for 3 or more weeks. The remaining 130 patients met criteria for bipolar disorder, all of whom had failed to respond to one or more trials with a mood stabilizer plus an antipsychotic. Clinical outcomes were determined by comparing changes on these behavioral scales between start of a treatment regimen and after 3 months of an unchanged regimen; scales were the 17-item Hamilton Depression Rating Scale (HAMD-17), Quick Inventory of Depressive Symptomatology (QIDS-C16), and Clinical Global Impression–Severity of Illness (CGI-S). Response was defined as 50% or greater reduction from the pretreatment HAMD-17 score, and remission was defined as a score of less than 7 on the HAMD-17 at the end point.
At baseline, the TRD group had, on average, moderate to severe depression (HAMD-17: 23.86), with scores on QIDS-C16 of 15.0 and on CGI-S of 5.2. The bipolar group had, on average, mild to moderate depression (HAMD-17, 18.3), with scores on QIDS-C16 of 12.3 and on CGI-S of 4.5. Clinical improvements in depression severity were seen with the different treatment strategies:
· Antidepressants plus antipsychotics produced significantly greater improvement on HAMD-17 for the TRD group (score, 9.2) vs. bipolar group (score, 5.1), but no significant differences on other scales: 5.6 vs. 4.5 on QIDS-C16 and 1.7 vs. 1.4 on CGI-S.
· Antidepressants plus mood stabilizers showed marginally greater improvement on HAMD-17 for the TRD group (score, 8.8) vs. the bipolar group (score, 6.3); the combination of antidepressants, antipsychotics, plus mood stabilizers also showed marginally significant differences between the TRD group (score, 9.3) and the bipolar group (score, 6.9) on the HAMD-17. But other clinical scales failed to reveal significant differences in outcomes.
Response and remission rates did not differ significantly between the two types of depression, nor did they differ based on any type of combination treatment. Response rates were 26% in the TRD group and 19% in the bipolar group for all treatment strategies; remission occurred in 5% of the TRD group and in 7% of the bipolar group. These low rates of remission reflect the refractory nature of depression in these patients.
These data, seen in a natural clinical setting, highlight the importance of augmentation strategies in depression. The study also showed that the reduction of depressive symptoms was greater in the TRD group compared with the bipolar group when pharmacologic combinations included an antidepressant and that adding an antidepressant to the treatment regimen for bipolar depression increased the risk of TEAS, cycle acceleration, and mood destabilization in these patients. Taken together, these results raise questions about the use of antidepressants in bipolar disorder. (Moderie, C., et al. (2022). Distinct effects of antidepressants in association with mood stabilizers and/or antipsychotics in unipolar and bipolar depression. J Clin Psychopharmacol, 42(2), 118–124. Retrieved May 2022 from https://journals.lww.com/psychopharmacology/Fulltext/2022/03000/Distinct_Effects_of_Antidepressants_in_Association.2.aspx)
Released: May 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
Atogepant and Sumatriptan Safe to Administer Together for Migraine
Acute treatment for migraine attacks includes triptans; the most commonly used triptan is sumatriptan. Preventive therapies are also beneficial; they may be used in those with severe or frequent migraine attacks and in those with a poor response to acute treatments. Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, has been approved as a preventive treatment for migraine; it can be expected, therefore, that it could possibly be given in combination with sumatriptan.
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An open-label, randomized, 3-way crossover study evaluated the possibility of how administering the two drugs together affected pharmacokinetic parameters, and compared how the body absorbed, distributed, and eliminated the two drugs when given together compared to each drug given alone. The trial enrolled 30 healthy adults, of whom 27 completed the study; 29 received a single oral 100-mg dose of sumatriptan, 28 received a single oral 60-mg atogepant dose, and 27 received the drugs administered together. Blood samples were drawn to determine plasma drug concentrations on days 1, 8, and 15, and safety and tolerability were monitored by physical exams, vital signs, clinical lab tests, and ECGs.
Most of the pharmacokinetic parameters were only minimally changed when atogepant was given with sumatriptan, compared to either drug given alone. The peak plasma concentration (Cmax) of atogepant was reduced by 22% when administered with sumatriptan. Coadministration delayed the median atogepant Tmax (time to maximum plasma drug concentration) by 1.5 hours. This lower Cmax and delayed Tmax could be attributed to the effect of sumatriptan on gastric emptying. However, these changes are expected to have minimal clinical relevance because use with sumatriptan was not shown to not affect the overall systemic exposure to atogepant.
These results allay concerns about the safety and tolerability of using these two antimigraine medications together, leading to more options for treating severe or frequent migraines. Further studies are needed to confirm these findings. (Boinpally, R., et al. (2021). Atogepant and sumatriptan: No clinically relevant drug-drug interactions in a randomized, open-label, crossover trial. Pain Management; 12(4), 499–508. Retrieved May 2022 from https://www.futuremedicine.com/doi/10.2217/pmt-2021-0073)
Released: May 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
Risk of Anaphylaxis after Second Dose of COVID Vaccine is Low in Those Who Had Such a Reaction to First Dose
One barrier to successful vaccination is the occurrence of rare adverse reactions to the vaccines, including severe allergic reactions, which occur in 7.9 per 1 million vaccinations. As the rollout for the SARS-CoV2 mRNA vaccines was underway, allergic reactions rapidly led to recommendations that people with an immediate allergic reaction to the first dose shouldn’t receive additional doses. But this places those people at risk of contracting the disease.
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A review article published in JAMA Internal Medicine examined 22 studies and asked the question: What is the risk of an immediate severe allergic reaction (anaphylaxis) to a second dose of a SARS-CoV2 mRNA vaccine among individuals who had an immediate allergic reaction of any severity to their first dose? The researchers examined studies conducted from the onset of COVID-19 vaccination through October 4, 2021; immediate allergic reaction was defined as one that occurred within 4 hours of the first dose. The individuals received the second vaccine under the supervision of an allergist.
The meta-analysis identified 1,366 individuals who had immediate allergic reactions to their first vaccination, among them, 78 persons who had suffered an anaphylactic reaction to the first dose. Of the 1,366 individuals, pooled analysis showed that 6 experienced severe immediate allergic reaction (absolute risk, 0.16%) and 232 developed mild immediate symptoms (absolute risk, 13.65%) to the second dose of the vaccine. Of the 78 persons who had suffered anaphylaxis after the first dose, 4 had a second severe allergic immediate reaction (absolute risk, 4.94%) and 15 had mild immediate symptoms (absolute risk, 9.54%). None of the 6 persons who experienced severe allergic reactions to the second dose died; 5 recovered after receiving IM epinephrine and the sixth recovered without treatment. Subgroup analysis, examining studies that permitted altered dosing, premedication before vaccination, or skin testing, didn’t result in alterations to these findings.
These findings contradict the common assumption that a history of allergic reactions guarantees another to subsequent vaccine exposure. In such individuals, consultation with an allergist before the second vaccination is recommended. (Chu, D. K., et al. (2022). Risk of second allergic reaction to SARS-CoV-2 vaccines: A systematic review and meta-analysis. JAMA Intern Med, 182(4), 376–385. Retrieved May 2022 from https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2788991)
Released: May 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
FDA Considering Changes to Improve Safe Disposal of Unused Prescription Opioid Analgesics
The FDA is seeking public comments until June 21, 2022, to a potential change to the Opioid Analgesic Risk Evaluation and Mitigation Strategy that would require that opioid analgesics used in outpatient settings be dispensed with prepaid mail-back envelopes and that pharmacists provide patient education on safe disposal of unused opioids. They seek comments from interested parties: patients, patient advocates, health care professionals, academics, researchers, pharmaceutical industry, and other government entities.
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The FDA’s efforts to address the opioid crisis include a focus on encouraging appropriate disposal of unused opioids. Current recommendations for disposal of unused drugs include permanent collection sites, such as kiosks in pharmacies or at community take-back events. If such opportunities aren’t available, the FDA recommends flushing those opioids on the Flush List (safe to be disposed in that way) or mixing with an unpalatable substance and disposing in the household trash. All these methods have their drawbacks, from environmental concerns to worries about safety to concerns about cost and inconvenience. Data show that educating patients about disposal options increases the disposal rate of unused medications; it’s hoped that providing an easy, cost-free option along with education will further increase that rate.
Patients commonly report having unused opioid analgesics after surgical procedures; studies show a range of 67% to 92% of patients, depending on the surgery, report excess opioid analgesics. Opioids used for chronic pain can also result in excess pills requiring disposal, due to changes in dose or medication, discontinuation of opioid treatment, or death of the patient. These unused opioids then end up sitting in their house, creating opportunities for nonmedical use, accidental exposure, overdose, and new cases of opioid addiction. Despite the risks associated with having unused opioid analgesics in the home, most studies found that fewer than 50% of patients report disposing of them. Patient education on the need to dispose of them has been shown to increase disposal rates; in one study that examined the effect of providing patient education, a take-home disposal method, or both, use of either intervention increased the disposal rate by about 12% and the combined intervention increased the disposal rate by 19.5%. It is reasonable to assume that mail-back envelopes are one such method that could increase this disposal rate.
The FDA is anticipating that this REMS-mandated disposal program could complement programs already in place. Recognizing that dispensing mail-back envelopes with every opioid prescription would be inefficient, the FDA proposes the use of algorithms that could enable pharmacists to target those prescriptions most likely to result in unused medications (that is, when filling new prescriptions for acute pain treatment or when changing the dose, medication, or formulation in a recurring prescription). (U.S. Food & Drug Administration. News Release. (2022). FDA considers new approach to improve safe disposal of prescription opioid analgesics, decrease unnecessary exposure to unused medication. Retrieved May 2022 from https://www.fda.gov/news-events/press-announcements/fda-considers-new-approach-improve-safe-disposal-prescription-opioid-analgesics-decrease-unnecessary; Federal Register. (2022). Providing mail-back envelopes and education on safe disposal with opioid analgesics dispensed in an outpatient setting; establishment of a public docket; request for comments. Retrieved May 2022 from https://www.federalregister.gov/documents/2022/04/21/2022-08372/providing-mail-back-envelopes-and-education-on-safe-disposal-with-opioid-analgesics-dispensed-in-an)
Released: May 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer