MENTAL HEALTH
Ketamine shows promising reduction of depression, suicidal thoughts
Ketamine therapy has a swift, short-term effect on reducing symptoms of depression and suicidal thoughts in patients, according to a new report in BJPsych.
Walsh et al. performed a systematic review of 83 papers that included 33 systematic reviews, 29 randomized controlled trials, 2 randomized controlled trials without placebos, 3 nonrandomized trials with controls, 6 open-label trials, and 10 retrospective reviews.
Overall, the reviewers found support for ketamine's robust, rapid, and transient antidepressant and antisuicidal effects. The reviewers considered studies that focused on specific psychologic states including unipolar depression and major depressive disorder (MDD), bipolar disorder, suicidal ideation, interactions with electroconvulsive therapy (ECT), social anxiety and generalized anxiety disorders (GADs), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and substance use disorders (alcohol, cocaine, opiates, and eating disorders).
In the studies that examined ketamine's effects on patients with unipolar depression and MDD, all participants noted the rapid onset of ketamine's antidepressant effect among patients with MDD and recorded a lower mean depression severity and remission in ketamine groups relative to placebo. The onset of ketamine's effects began between 1 hour and 24 hours after I.V. infusion and lasted for about 1 to 2 weeks. Repeated administrations up to six doses produced a greater antidepressant effect at a 2-week follow-up.
Seventeen systemic reviews-of which 9 included meta-analyses-indicated that ketamine induced rapid and short-lived antidepressant effects in patients with unipolar and bipolar disorders. Effects began as early as 4 hours postinfusion, were consistent by a 24-hour postinfusion measurement, and lasted anywhere from 3 days to 7 days. Meta-analyses at 14 days did not find a ketamine effect superior to placebo. Unfortunately, there were no consistent results in effect size in either the unipolar or bipolar group.
Ketamine treatment was associated with a moderate-to-large decrease in suicidal ideation within 4 hours of infusion and maintained for 3 days to 1 week. Remission of suicidal ideation after ketamine treatment persisted for up to 1 week in approximately 85% of patients. Ketamine's effects remained significant even after adjusting for depression change.
The authors say that combined anesthetic and antidepressant action of ketamine would be a logical choice for patients undergoing ECT because it could exert additive synergistic effects.
Retrospective analysis of six studies that examined ketamine's influence on patients with social anxiety and GAD found that the drug induced a significant decrease in anxiety following treatment compared with baseline. Higher doses of ketamine (1 mg/kg) were found to have the greatest and most durable anxiolytic effects.
Patients with OCD who received ketamine infusion also scored lower on OCD scores than those who received placebo at 4 hours and 7 hours after treatment. Half also demonstrated at least a 35% reduction in OCD compared with the placebo group.
Ketamine was shown to significantly decrease PTSD and depression by a 24-hour postinfusion mark and 80% remission at a 14-day follow-up in eight publications reviewed by Walsh, et al.
Regarding substance use disorders, 70% of participants in one study remained abstinent from alcohol after 1 year posttreatment versus only 24% of participants who only received aversion therapy. In three studies examining cocaine abuse, a single dose of ketamine at 0.41 mg/kg increased motivation to quit use and reduce cue-induced cravings significantly more than lorazepam at 24-hour follow-up. A second dose (0.71 mg/kg) further decreased cravings for an additional day after administration. Cravings for opioids were reduced in patients who received 2 mg/kg or 0.2 mg/kg, though the group receiving the high dose also showed a greater reduction in cravings. The high-dose group sustained reduced cravings for 24 months after treatment, whereas cravings in the low-dose group did not last beyond 1 month. Finally, a ketamine infusion of 20 mg/h for 10 hours showed a marked and sustained return to normal eating behavior and acceptance of normal weight in patients with eating disorders.
Reference: Walsh Z, Mollaahmetoglu OM, Rootman J, et al. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsych Open. 2022;8(1):e19. doi:10.1192/bjo.2021.1061.
HIV TREATMENT
New injectable PrEP treatment approved
The FDA has approved cabotegravir (Apretude, ViiV Healthcare) for adults and adolescents at risk for contracting HIV-1 infection.
Cabotegravir is an HIV-1 integrase strand transfer inhibiter and the first long-active injectable for HIV preexposure prophylaxis (PrEP) approved by the FDA. It is administered in 600 mg (3 mL) injections 1 month apart for 2 consecutive months after an oral lead-in, if used and every 2 months thereafter.
"[This] approval adds an important tool in the effort to end the HIV epidemic by providing the first option to prevent HIV that does not involve taking a daily pill," said Debra Birnkrant, MD, director of the Division of Antivirals in the FDA's Center for Drug Evaluation and Research in a press release. "The injection, given every two months, will be critical to addressing the HIV epidemic in the US, including helping high-risk individuals and certain groups where adherence to daily medication has been a major challenge or not a realistic option."
The safety and efficacy of cabotegravir were examined in two trials. The first trial included 4,556 HIV-uninfected cisgender men and transgender women who have sex with men and have high-risk behavior for HIV infection. The second trial included 3,224 cisgender women at risk for HIV infection.
In both trials, participants were separated into two groups: one that received cabotegravir and one that received Truvada. The cabotegravir group began treatment with a daily oral 30 mg tablet and a placebo for up to 5 weeks. This was followed by a cabotegravir 600 mg injection at 1 and 2 months after the start of treatment and then every 2 months thereafter along with a daily placebo tablet.
The Truvada group in both trials received an oral Truvada tablet and placebo tablet daily for 5 weeks. Then, participants took oral Truvada and a placebo I.M. injection after 1 and 2 months of the start of treatment, then every 2 months thereafter.
In the first trial, cabotegravir showed a 69% reduction in risk of HIV infection when compared with Truvada. In the second trial, participants taking cabotegravir showed a 90% reduction in risk of infection with HIV compared with Truvada.
Prescribing information for cabotegravir includes a boxed warning that individuals must be tested for HIV-1 prior to the initiation of oral or injectable forms and before each subsequent injection.
Cabotegravir is contraindicated in individuals with unknown or positive HIV-1 status, previous hypersensitivity to cabotegravir, and those already taking medications that could cause significant decreases in cabotegravir plasma concentrations. Cabotegravir should not be used in conjunction with drugs that induce uridine diphosphate glucuronosyltransferase-an enzyme involved in drug metabolism and may significantly decrease plasma concentrations of cabotegravir.
Adverse reactions reported throughout trials with cabotegravir include injection-site reactions, diarrhea, headache, pyrexia, fatigue, sleep disorders, nausea, dizziness, flatulence, abdominal pain, vomiting, myalgia, rash, anorexia, somnolence, back pain, and upper respiratory tract infections.
References: U.S. Food and Drug Administration. FDA approves first injectable treatment for HIV pre-exposure prevention. 2021. http://www.fda.gov/news-events/press-announcements/fda-approves-first-injectable.
Apretude (cabotegravir) label - http://accessdata.fda.gov. http://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215499s000lbl.pdf.
BREAST CANCER
FDA grants breakthrough drug designation
The US FDA has granted breakthrough therapy designation to Trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) for the treatment of adults with unresectable or metastatic HER-2 positive breast cancer who received two or more prior anti-HER2-based regimens in the metastatic setting.
The designation was granted based upon results from a randomized phase 3 DESTINY-Breast03 trial that enrolled approximately 500 patients from North America, South America, Europe, Asia, and Oceania with either positive unresectable or metastatic breast cancer previously treated with trastuzumab (Herceptin, Genentech) and a taxane. Trastuzumab deruxtecan was compared with HER2-targeted antibody-drug conjugate, ado-trastuzumab emtansine (Kadcyla, Genentech).
The study's primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. The secondary endpoints were overall survival, objective response rate, duration of response clinical benefit rate, investigator-assessed PFS, and safety.
Results from the trial showed an overall reduced risk for progression or death by 72% (HR = 0.28; 95% CI, 0.22-0.37). More patients assigned trastuzumab deruxtecan than ado-trastuzumab emtansine achieved confirmed objective response (79.7% versus 34.2%) and remained alive at a 1-year mark (94.1% versus 85.9%).
Trastuzumab deruxtecan is to be administered as an I.V. infusion only and not I.V. push or bolus. Patients with breast cancer should receive an I.V. infusion of 5.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity.
There are no contraindications for Trastuzumab deruxtecan.
Adverse reactions reported with the use of Trastuzumab deruxtecan for patients with breast cancer include nausea, leukopenia, decreased hemoglobin, neutropenia, fatigue, vomiting, alopecia, increased aspartate aminotransferase, increased alanine aminotransferase, thrombocytopenia, constipation, anorexia, anemia, diarrhea, hypokalemia, and cough.
References: Safety Data: ENHERTU: HCP. ENHERTU. http://www.enhertuhcp.com/en/breast/efficacy/safety-data.
HemOnc Today. ENHERTU receives breakthrough therapy designation for second-line breast cancer treatment. Healio. http://www.healio.com/news/hematology-oncology/20211229/ef-ra-enhurtu-reveives-b.