SSRIs May Increase the Risk of Violent Behavior in Young People

Selective serotonin reuptake inhibitors, or SSRIs, are among the most commonly prescribed antidepressants. These drugs are not generally used in adolescents and young adults as several studies have suggested that SSRIs increase the risk of suicidal ideation in these age groups, but not in adults. SSRIs are also believed by some to cause violent behavior, particularly in adolescents and young adults, although the data on this is much more inconclusive. Therefore, one group of researchers in Sweden designed a study to try and determine a possible correlation between SSRI use and violence in adolescents. The researchers used records available from the Swedish Prescribed Drug Register to identify 856,493 patients over the age of 15 who had been prescribed SSRIs in the period between January 1, 2006 and December 31, 2009. The researchers then examined the arrest records of these patients and compared individual patient records when they were on SSRI treatment to when they were not on an SSRI treatment.

Of the entire patient population studied, 9.9% were between the ages of 15 and 24, and these individuals were considered adolescents or young adults. Upon examining the arrest and conviction records of this population, it was determined that this group was more likely to be convicted of a violent crime while on SSRI treatment, although only low doses of SSRIs produced this result. Patients in this age group on moderate or high doses of SSRIs and patients in other age groups on any dose of SSRI did not show a significant increase in violent crime. Within the 15 to 24 age group, the use of medications that could serve as an alternative to SSRIs, such as venlafaxine, was also associated with an increase in violent crime. The study could not determine the cause of this association, and recommended that further studies should be conducted to corroborate their findings.

Given their potential to increase suicidal ideation and possibly the rate of violent crime among adolescents and young adults, is there any case for using SSRIs in adolescents? Would giving a young person large doses of an SSRI really be the most effective treatment option?  With this study’s suggestion that other antidepressant treatments may also increase violent behavior in adolescents, is it possible that antidepressant medication as a whole may not be appropriate for adolescents or young adults?

 

 

Molero Y, Lichtenstein P, Zetterqvist J. Selective serotonin reuptake inhibitors and violent crime: a cohort study. PLoS Med. DOI: 10.1371/journal.pmed.1001875 (published 15 September 2015)

Cognitive Effect of Antihypertensive Treatment Discontinuation in Elderly Patients

Although having a midlife higher blood pressure is associated with a greater risk of cerebrovascular disease and subsequent cognitive decline later in life, the effect of later in life blood pressure on cognition is not as clear. Several reviews of observational studies suggest that higher blood pressures later in life may decrease the risk of cognitive decline, as higher blood pressure may be needed to ensure proper blood flow to the brain. In order to test the effect of late in life blood pressure on cognition, a study was conducted on 356 patients in the Netherlands. These patients needed to be at least 75 years old, had to be on some form of hypertension treatment, had to have a systolic blood pressure of 160 or less, and also had have some mild cognitive impairment. 180 of the patients were discontinued from their antihypertensive treatments, while 176 patients continued their treatments. Patients were studied for a total of 16 weeks, and all patients had their cognitive status and blood pressure checked at weeks 6, 10, and 16. Cognitive status was determined by using the Mini-Mental State Examination.

At the end of the study, the patients who had discontinued their antihypertensive treatments showed an increase in blood pressure compared to the control group, which would be expected. However, the two groups did not show a statistically significant difference in cognitive function, and also had no significant difference in the adverse events reported. Therefore, the study concluded that discontinuing antihypertensive treatment does not improve cognitive function in elderly patients after 16 weeks, but also recognized that future trials with longer follow-ups would be needed to support this finding. Given the seemingly conflicting nature of the observational study reviews and the results of this study, is it possible that lower blood pressure later in life may not have a causal relation on cognitive decline, and if not could these factors have similar causes? Given the currently conflicting data on the effect of later in life blood pressure on cognition, should an elderly hypertensive patient’s cognitive status be considered when suggesting treatment plans and blood pressure goals?

Moonen J, Foster-Dingley J, Ruijter W. Effect of discontinuation of antihypertensive treatment in elderly people on cognitive functioning-the dante study leiden. JAMA Intern Med. 2015;175:1622-1630.

Ultra-Low Doses of Opioids May Treat Suicidal Thoughts

Suicide leads to over 1 million deaths worldwide every year and is preceded by suicidal thoughts, although it is only rarely that suicidal thoughts lead to a completed suicide. Given the prevalence of suicide, the treatment of suicidal thoughts should be an important task for healthcare providers. However, there are currently no short term, medication based treatments for suicidal thoughts that can be easily administered independently in an outpatient setting and which can be effective for a wide range of patients. Therefore, one study was designed to test the effectiveness of very low doses of the opioid buprenorphine in quickly treating suicidal thoughts.

The study followed 88 patients selected from the populations of four medical centers in Israel. Participants were selected based on their suffering from clinically significant suicidal ideation and could not have a history of opioid abuse. 57 patients received buprenorphine treatment while 31 received a placebo, and both groups had their amount of suicidal thoughts as well as their likelihood to commit suicide measured over the course of four weeks. At the end of the study, patients in the buprenorphine group had a significant decrease in suicidal thoughts compared to the placebo group, although this group also exhibited an increased number of side effects, particularly fatigue, nausea, dry mouth, and constipation. At the end of the study, both groups were slowly tapered off of their medications, and no participant in either group reported feeling withdrawal symptoms. This study suggests that buprenorphine may be an effective short term treatment of suicidal thoughts. Although it is important to treat suicidal thoughts, is doing so by increasing the number of prescribed opioids the most effective method of doing this?

 

Yovell Y, Bar G, Mashiah M. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry. DOI:10.1176/appi.ajp.2015.15040535

Effect of Metformin on Overweight Adolescents with Type 1 Diabetes

Although the common idea is that someone suffering from type 1 diabetes would be skinny, data from the Type 1 Diabetes Exchange Clinic indicates that 39% of adolescents with type 1 diabetes are overweight or obese. Being overweight with type 1 diabetes may require higher doses of insulin to achieve proper glycemic control, and is also associated with increased risk of cardiovascular disease. Therefore, overweight adolescents may benefit from additional treatments in addition to insulin, and one study sought to examine the efficacy of metformin as an additional treatment of overweight adolescents. Metformin is commonly used to treat type 2 diabetes, and other studies suggested it could lower the doses of insulin needed in adult patients with type 1 diabetes but the studies on adolescents had been inconclusive.

The study was conducted on 140 patients with type 1 diabetes who were between the ages of 12 and 20 and who had a BMI in the 85th percentile or greater. Half of the participants were given metformin that was titrated up to a 2000 mg dose, while the other half of the participants were given a placebo. After 26 weeks, the participants had their A1C levels measured against the baseline that was collected at the beginning of the study. Also examined were the patient’s daily blood glucose readings and their BMI at the end of the 26 weeks.

At the end of the 26 week study, both the metformin and the placebo groups had seen increases in A1C levels by .02% from the baseline, and the blood glucose monitoring also showed no significant differences between the groups. The metformin group did show a greater amount of participants who decreased their daily levels of insulin as well as a larger number of participants who lost weight. However, the metformin group also had a much larger incidence of gastrointestinal upset than the placebo group, and also caused several instances of hypoglycemia in patients. The article concluded that metformin should not be prescribed for overweight adolescents, because it did not improve glycemic control, had only limited benefits, and caused an increased risk of gastrointestinal upset and hypoglycemia. This study was interesting in that it studied the efficacy of a drug used commonly in type 2 diabetes patients on type 1 patients instead. Should there be more research into examining the effects of current medications on type 1 patients, or would the time and money used for those studies be better spent on trying to find new treatments for diabetes?

Libman I, Miller K, DiMeglio L. Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes. JAMA. 2015;314:2241-2250. doi:10.1001/jama.2015.16174.

Opioid Prescription after Overdose Associated with Repeated Overdose

The use of prescription opioids has increased greatly in the last several years, which has led to a nearly parallel rise in the amount of opioid abuse and overdose. One study sought to examine how patients who had overdosed on opioids continued to use opioids after their overdose. For the study, the authors selected, based on the claims of a large U.S. health insurer, 2,848 patients who had been prescribed long term opioid therapy for noncancer pain and who had overdosed. The patients’ medical history was examined starting 90 days before the overdose and ending at one of the stopping criteria. The stopping criteria were that 2 years had passed since the overdose, the patient experienced a second overdose, the patient switched insurance companies or entered Medicare, or that the study had ended.

In order to compare patients taking different opioids, the study calculated each patient’s morphine-equivalent dosage (MED) and then calculated the average MED for a patient at times relative to their overdose. Generally, a patients MED increased greatly the week leading up to the overdose before peaking at the time of the overdose. The MED would then drop off quickly after the overdose before returning to a stable plateau slightly lower than the MED before the overdose. This plateau after the overdose was related to another finding of the study, which was that 91% of opioid overdose patients received a prescription for an opioid after their overdose. Those patients who received a prescription for a higher dose of opioids had a repeated overdose in 17% of cases, compared those who were prescribed lower doses repeatedly overdosing in 9% of cases. Both of these are greater than the 8% of patients who had a repeated overdose without an opioid prescription. Of those patients receiving a prescription, 70% received it from the same physician that had prescribed them their opioids before the overdose.

This study demonstrates two potential areas of improvement when treating opioid overdoses. There should be better and more targeted treatments for the substance abuse issues that lie behind many opioid overdoses. This study was limited in that it was unable to identify patients receiving methadone or buprenorphine treatment for opioid abuse, but the expansion of treatment programs such as these may help cut down on the amount of opioid overdoses. The establishment of a system where reporting opioid overdoses to a department of public health or other, similar agency would help target patients who could most benefit from these types of therapy. This could also assist prescribers in cutting down on the amount of post-overdose opioid prescriptions, which are associated with higher risks of repeated overdoses.

 

Larochelle MR, Liebschutz JM, Zhang F. Opioid prescribing after nonfatal overdose and association with repeated overdose: a cohort study. Ann Intern Med. 2016;164:1-9.

Comparing the Efficiency of Medication Therapy Management Reimbursement Methods

With the current transition away from a fee-for-service payment system, a major question for many pharmacists is how they will be compensated for providing services, such as medication therapy management, which may not traditionally be associated with a pharmacist. One study compared two potential methods of reimbursement by examining MTM encounters at the University Of Minnesota Duluth College Of Pharmacy. The two methods that were examined were a time-based billing method, based solely on the length of the encounter, and a resource-based relative value scale, or RBRVS, which incorporates the number of drug therapy problems and the complexity of the care plan as factors in reimbursement. This study specifically used the RBRVS system designed by the Minnesota Department of Human Services, which had 5 levels of service that could be billed.

In order to compare the efficacy of these two systems, 525 MTM encounters from a span of 6.5 years and were selected. The average length of these encounters was 45 minutes and the patients had an average of 12 medications. These encounters then had a billing cost calculated using both the time-based method and the RBRVS method. The average billing amount for these encounters using the time-based model was $111.83, which was significantly higher than the average amount for the RBRVS method, $83.71. The authors of this study suggest that the RBRVS method does not take into account the potential monetary benefits of improved patient health after the MTM services, which could be a potential source of improvement for the RBRVS system. This study also suggests that the limited number of levels of service restricts the ability of the RBRVS system to accurately bill the amount that is actually required to perform MTM services. The RBRVS method was developed as an attempt to correct inconsistencies in payment for services like MTM, but if it leads to underpayment of service providers then its use may make MTM clinics financially unsustainable. Given these problems, is it possible to revise the RBRVS method so that it can be a more accurate billing method, or should it be abandoned in favor of a time-based billing method? Could there be a third billing method that might be even more accurate?

Hager K, Gosser R. Restropective analysis of billing at a standalone medication therapy management clinic. Am J Health Syst Pharm. 2016;73:77-81

Newly Approved Protease Inhibitor Demonstrates Novel Route of Administration in the Treatment of Multiple Myeloma

Multiple myeloma is a common form of blood cancer that is diagnosed in about 86,000 people per year. The most commonly used treatments for multiple myeloma are protease inhibitors, or PIs. The first PI, bortezomib, was approved by the FDA in 2003 and can be administered intravenously to induce apoptosis in cancer cells by binding to and inhibiting the β5 site of the 20s proteasome. Bortezomib has several significant drawbacks, including the risk for peripheral neuropathy and the development of resistance and subsequent relapse for a majority of patients on this treatment. A second generation PI, carfilzomib, was introduced in 2012 and although it has a smaller risk of causing peripheral neuropathy it must still be administered intravenously.

Ixazomib, another second generation PI that was approved by the FDA in November 2015, represents a significant improvement over the previously available PIs. Ixazomib has a similar mechanism of action to bortezomib, but its higher specificity to the β5 site of the 20s proteasome means that ixazomib has a much lower incidence of peripheral neuropathy.  However, despite the similar mechanisms of action ixazomib may be used to treat bortezomib resistant patients. Perhaps the most important characteristic of ixazomib is its ability to be taken as an oral capsule as opposed to the intravenous administration that is required for other PIs. The most common side effects of orally administered ixazomib were manageable side effects, such as nausea and diarrhea. Treatment with ixazomib demonstrated a response in 34% of patients in the Phase II studies, and concurrent treatment of ixazomib and dexamethasone demonstrated a response in a further 34% of the population. Based on its mild side effects, efficacy, and convenience of administration, ixazomib represents a promising agent in the treatment of multiple myeloma. Perhaps this study demonstrates the need for further research into the development of more convenient, orally administered treatments to replace medications traditionally administered intravenously?

 

Muz B, Ghazarian RN, Ou M, et al. Spotlight on ixazomib: potential in the treatment of multiple myeloma. Drug Des Devel Ther. 2016;10:217-226

Correlation between Proton Pump Inhibitor Use and the Development of Chronic Kidney Disease

Proton pump inhibitors, or PPIs, are a class of drugs commonly prescribed to treat GERD and that had over 15 million users in America in 2013.  These drugs have been known to cause adverse side effects, including acute kidney injury. Based on this potential for kidney damage, a group of researchers developed a study to test their hypothesis that the use of PPIs was correlated to an increase in kidney ailments, particularly chronic kidney disease, or CKD. The study compared 10,482 patients who received either PPI therapy, H2 Receptor Antagonist Therapy, or no therapy. These patients were selected from communities in four different states, and the trials were carried out by six different universities located in these communities who studied patients over a median of 13.9 years per patient. Patient medication use was determined primarily by an annual over the phone follow ups, with patients also being asked to visit researchers a total of five times with at least three years between each visit, starting in 1987 and ending in 2013.

This study determined that patients using PPIs were 1.45 times as likely to develop CKD as a patient who was taking H2 Receptor Antagonist therapy or no therapy. A second study was conducted by the Geisinger Health System, which examined 248,751 patients for a mean of about six years per patient. This study also determined that PPI use increased the likelihood of developing CKD, while neither study suggested that H2 Receptor Antagonist use was associated with an increased risk of CKD. These studies demonstrated a correlation between PPI use and CKD development, but further studies would be needed to determine if the cause of kidney damage is actually the PPI. However, these studies suggest caution may be appropriate when recommending PPI therapy, and may also necessitate further study and research into whether over the counter PPIs need additional regulation in order to cut down on the prevalence of CKD.

 

Lazarus B, Chen Y, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. doi:10.1001/jamainternmed.2015.7193 (Published 11 January 2016).