By: Jennifer Tran, PharmD; PGY1 Pharmacy Resident
Mentor: Lisa Sterling, PharmD, BCPS, BCGP; Residency Program Director/Clinical Pharmacy Specialist, Mercy Hospital – Springfield, MO
Program Number: 2020-11-03
Approval Dates: December 1, 2020 to May 1, 2021
Approved Contact Hours: 1 hour
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Psychiatric disorders affect 450 million people across the world.1 According to the World Health Organization (WHO), one in four people will have one or more mental disorders in their lifetime.1 Listed in Table 1 are common risk factors for psychiatric disorders:
Medications used to treat a variety of major psychiatric disorders include antipsychotics, antidepressants, mood stabilizers, and anti-anxiety, however the efficacy of these medications varies and many of them have significant adverse effects. Treatment failure and adverse effects along with significant adherence issues lead to many patients with psychiatric disorders needing adjunctive or alternative therapy. As a result, several nontraditional medications have been investigated in psychiatric disorders with sufficient data for some of these medications to be included in clinical guidelines. This article will discuss medications that have been investigated in the treatment of major depressive disorder, anxiety disorders, schizophrenia, and bipolar disorder.
Patients with major depressive disorder feel persistently depressed or lose interest in activities. Despite the numerous antidepressant medications, remission in depression is difficult to achieve. Failure to respond to antidepressants leads to the diagnosis of treatment resistant depression and may result in treatment with alternative medications. In the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trials, researchers evaluated the effectiveness of antidepressants in clinical practice. The first study found that only 25-33% of patients achieved remission in the first 14 weeks of therapy.2 The number of patients who fail to achieve remission continues to decrease after consecutive trials of antidepressants in later stages.3 The STAR*D trial shows that patients who progressed through the treatment algorithm were at high risk for relapse during the follow-up phase.3 These trials show how difficult depression may be to treat due to lack of efficacy.
Generalized anxiety disorder is characterized by excessive, uncontrollable, or irrational worry about events or activities. Medications used for depression have also demonstrated efficacy in anxiety and are used as first line agents in anxiety, as serotonin regulates both fear and worry in the amygdala.4 Anxiety can be difficult to treat. In a systematic review, remission of anxiety symptoms varied between antidepressants with fluoxetine having the highest remission rate (60.6%) and escitalopram having the second highest remission rate (26.7%). 5
In schizophrenia, patients are not in touch with reality due to psychotic symptoms such as hallucinations or delusions. This occurs due to increased levels of dopamine in the brain. First line treatment for schizophrenia is antipsychotics. However, these medications have been shown to have high discontinuation rates and adherence is difficult to achieve. In the landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trials, more than 60% of patients discontinued their antipsychotic medication due to lack of efficacy, intolerance, patient’s decision, or other reasons.6 In a systematic review, clinicians estimated that approximately 40% of schizophrenia patients were nonadherent to their medications. Factors that may be associated with nonadherence include poor insight, negative attitudes towards medications, or inadequate discharge planning.7
In bipolar disorder, patients experience extreme mood shifts that can lead to manic symptoms including delusions of grandiosity, extremely easy distractibility, and flight of ideas. Bipolar disorder tends to have a higher risk of relapse in comparison to other psychiatric disorders.8 Nonadherence may be attributed to bipolar patients’ risk of relapse. In this patient population, nonadherence rates are approximately 50%.8 Factors that may influence nonadherence include negative attitudes towards medication, severity of illness, complexity of medication regimen, and side effects.8 Antipsychotics and mood stabilizers are two medication classes used to treat bipolar disorder. Mood stabilizers are used to prevent and treat mania. The purpose of this class is to stabilize a patient’s emotions from intense mood shifts.4
Anticonvulsants affect four main molecules which may have a role in treating bipolar disorder: GABA, excitatory amino acids like glutamate, dopamine, and serotonin.10 Anticonvulsant medications used to treat bipolar disorder represent some of the first alternative agents used in psychiatric disorders. Specifically, anticonvulsants that have shown a high level of efficacy in stabilizing mood in bipolar disorder include carbamazepine, lamotrigine, and divalproex sodium.4 Carbamazepine and valproate were the first anticonvulsant agents to be studied in treating the manic phase of bipolar disorder. This led to the investigation of other anticonvulsant agents in treating bipolar disorder. Not all anticonvulsants have been found to be efficacious, as each anticonvulsant has a different mechanism of action.
Valproic acid’s mechanism of action in bipolar disorder may be due to its diminished flow of sodium through voltage-sensitive sodium channels. The result of less sodium release leads to diminished release of glutamate. Another possible theory could be due to valproate increasing the release of GABA. Carbamazepine acts differently compared to valproic acid, as it works by binding to the alpha subunit of voltage-sensitive sodium channels. This leads to enhancing the inhibitory effects of GABA.4 Another anticonvulsant used in bipolar disorder is lamotrigine, which is specifically indicated for bipolar depression. Lamotrigine, like carbamazepine, blocks the alpha subunit of voltage-sensitive sodium channels. However, the mechanism of action in treating bipolar depression with lamotrigine may be due to its ability to reduce the release of glutamate. Lamotrigine has not been found as effective in treatment of mania as carbamazepine.4
Other anticonvulsants have been investigated in psychiatric disease states. Pregabalin and gabapentin have demonstrated no significant efficacy as a mood stabilizer4 but may have a role in anxiety. The mechanism of action in bipolar disorder of both gabapentin and pregabalin are thought to be due to binding selectively to voltage-sensitive calcium channels, which inhibits the release of excitatory neurotransmitters.4 Pregabalin is a GABA analog and recommended as first-line treatment in Canadian guidelines for social anxiety disorder and generalized anxiety disorder.11 Pregabalin was found to be superior to placebo in two randomized control trials, but the response rate was low at 30-43% compared to 20-22% for placebo.11 The anxiety effects of pregabalin relieved symptoms quickly. Pregabalin is a schedule V medication and should be used with caution in patients with a history of substance use disorder. Gabapentin has been shown to relieve symptoms of social phobia or social anxiety disorder. In a double-blind, placebo-controlled trial, 69 patients were randomized to receive either gabapentin flexibly dosed 900-3600mg/day in three divided doses or placebo for 14 weeks. A significant reduction of symptoms and a higher response rate was shown in the group that received gabapentin (32%) compared to those who received placebo (14%).12 Side effects were more frequently with gabapentin including dizziness and dry mouth. The response rate to gabapentin is low but provides a treatment option for those who are unable to tolerate a SSRI or at risk of dependence with benzodiazepines.
Ketamine has demonstrated anti-depressive effects, which are thought to result from glutaminergic N-methyl-D-aspartate (NMDA) receptor antagonism. In a systematic review of parallel-group or cross-over randomized controlled trials that compared single-dose intravenous ketamine to placebo in patients with unipolar or bipolar depression. The primary outcome was symptoms change measured by Hamilton Depression Rating Scale (HAM-D) or Montgomery-Asberg Depression Rating Scale (MADRS). The review found that ketamine was statistically significant in reducing depression in comparison to placebo at 40 minutes of infusion (p<0.001) and lasting until days 5-8.13 The systematic review showed that ketamine has an ultra-rapid effect on improving depressive symptoms. In a single-site, active placebo control, randomized, double-blind crossover study, forty-one patients suffering from treatment-resistant depression with single infusions of ketamine or midazolam. After patients relapsed with depressive symptoms, they received 6 open-label ketamine infusions three times a week for 2 weeks. Ketamine infusion was found to significantly reduce depressive symptoms with 59% of patients meeting response criteria (>50% decrease MADRS score 24 hours post infusion). This study showed how ketamine infusion can quickly reduce depressive symptoms, as well as maintain cumulative and sustained antidepressant effects with repeated infusions.14 Although the trial showed fast improvement in depressive symptoms there is a possibility of the placebo effect, which is high during the first couple of weeks of treatment. Long-term studies are needed to determine if ketamine infusion should be used as a treatment option. The efficacy of ketamine has led to the development of esketamine (Spravato®) specially for the treatment of major depressive disorder.
Dextromethorphan has been investigated as a treatment for depression and, like ketamine, is a NMDA receptor antagonist. Dextromethorphan also has an effect on serotonin and norepinephrine. Recently, the results of the GEMINI study were released in a press release. This was a Phase III randomized, double-blind, placebo-controlled, multi-center trial completed in the United States. The study randomized 327 patients with moderate to severe major depressive disorder to receive either dextromethorphan/bupropion modulated delivery tablet or placebo once daily for the first 3 days and twice daily thereafter for a total of 6 weeks. The active drug combination was found to be statistically significant in reducing the MADRS score compared to placebo (16.6 vs 11.9, respectively).15 In a phase IIA, open-label clinical trial, the efficacy and tolerability of the combination of dextromethorphan 45 mg and quinidine 10 mg twice daily over a 10-week period in 20 patients with treatment resistant depression was investigated. The researchers found that the treatment group statistically significantly reduced the MADRS score by -13 (p<0.001). Although the results show promise in reducing depression, tolerability may be an issue as 30% of patients discontinued treatment. The treatment was discontinued primarily due to tolerability. 16
Two anti-hypertensive agents’ prazosin and propranolol are frequently used to treat symptoms of psychiatric disorders. Prazosin is used to treat post-traumatic stress disorder (PTSD) induced nightmares. The mechanism of action is due to its alpha-1 adrenergic antagonism that reduces adrenergic response in the central nervous system. Thus, relieving symptoms of PTSD due to overstimulation of adrenergic activity.17 The use of this medication is controversial due to its place in the Veterans Affairs and Department of Defense (VA/DOD) guidelines, which do not include recommendations for or against the use of prazosin in PTSD associated nightmares.18 Smaller trials had shown promising results in reducing nightmares in PTSD patients. A larger, VA multi-site trial with 304 subjects found that prazosin failed to separate from placebo in treatment of global symptoms of PTSD and nightmares. The Prazosin and Combat Trauma PTSD trial (PACT) was a 26-week, multicenter, double-blind, randomized, controlled trial. Investigators found that there was no significant difference between the prazosin and placebo groups in the PTSD scale, sleep quality index, and global impression of change score. 19 In conclusion, they found that prazosin did not reduce symptoms of distressing dreams or improve sleep quality. Although there is conflicting evidence for the use of prazosin PTSD, pharmacists may continue to see it used.
Propranolol is a highly lipophilic beta receptor blocker, a property allowing it to cross into the blood brain barrier. Propranolol is used to treat the physical symptoms of performance anxiety including tremor, tachycardia, and sweating. The medication is dosed initially at 10mg/day as needed to a target of 10-40mg/day.17 Propranolol only reduces the physical symptoms of performance-anxiety but does not treat the underlying anxiety.
Anti-inflammatory and Salicylic Acid Agents
Inflammation has been shown to play a major role in depression, schizophrenia, and bipolar disorders. This is thought to be due to dysregulation of immune response leading to abnormal pro- and anti-inflammatory cytokine findings in patients.20 In depression, the theory of increased inflammation and an altered immune response has led to the investigation of non-steroidal anti-inflammatory agents (NSAIDs) as possible treatment options. Along with inflammation having a role in depression, specifically COX-2 inhibitors have been shown to have direct effects on the serotonergic system by increasing serotonin levels in rats.21 Celecoxib, a selective COX-2 inhibitor, was used to augment the SSRI sertraline over 8 weeks of therapy in female patients experiencing a first episode of major depression. Patients were randomized to receive either sertraline (up to 100mg/day) plus celecoxib 200mg/day or sertraline plus placebo. Both groups showed improvement with the celecoxib group having a greater decrease in HAM-D.21 During week 4, the difference in the change in the HAM-D score was statistically significant and in favor of the treatment group (-13.7 in the treatment group vs -8.8 in placebo, p=0.021). However, the investigators did not provide p values for week 8. Another double-blind, randomized controlled trial with similar findings looked at another selective serotonin reuptake inhibitor (SSRI), fluoxetine 20-40mg/day. Celecoxib was dosed higher in this trial at 400mg/day. Both groups showed a decrease of the HAM-D score, but the celecoxib group showed greater improvement in symptoms (p=0.04).22,23
Aspirin has been studied in the treatment of depression. In a randomized clinical trial, 100 patients with major depressive disorder were assigned to either aspirin plus sertraline (treatment group) or placebo plus sertraline for 8 weeks. Mean Beck Depression Inventory (BDI) scores for depression severity were statistically significantly lower in the aspirin treated group (p=0.001). Both groups were similar in terms of side effect profile with more than half of the aspirin group (64%) not experiencing side effects at all.24 Key points to consider with this trial is that depression in the placebo group was more severe in comparison to the treatment group, which could have influenced results.
Pramipexole is a dopamine agonist at the D2 and D3 receptors and used in the treatment of Parkinson’s disease and restless leg syndrome. It has been demonstrated efficacy as a treatment option in treatment-resistant depression and bipolar depression I. One of the most common symptoms with depression is anhedonia or loss of interest in activities. Anhedonia has been associated with decreased levels of dopamine.25 In 60 patients with treatment-resistant major depressive episode, flexibly dosed pramipexole was added to standard antidepressant treatment in an 8-week, randomized, double-blind, placebo-controlled trial. The standard antidepressant therapy included both SSRI’s and serotonin-norepinephrine reuptake inhibitor (SNRI). The mean dose of pramipexole as augmentation was 1.35 mg/day. The primary outcome was change in MADRS score. Mixed-effects linear regression model was used to determine the change in MADRS. The results found a statistically significant time effect favoring pramipexole (p=0.038). However, response (p=0.27) and remission (p=0.61) comparing pramipexole to placebo was not statistically significant.26
Estrogen and Progesterone Agents
The onset of schizophrenia for women commonly occurs five years later in comparison to men which have an earlier onset at usually in their 20’s. Women with schizophrenia are more vulnerable or at risk for relapse during the postpartum period after pregnancy or during menopause when estrogen levels are down.27 In a dose-finding, double-blind, placebo-controlled study, adjunctive transdermal estradiol 100 mcg compared to placebo was investigated in 102 female child-bearing schizophrenia patients for 28 days. The results showed the addition of estradiol significantly reduced positive and general symptoms on the psychopathological symptom ratings (PANSS subscale scores) compared to women who received antipsychotic medication alone (p<0.05). 27 This trial included primarily a younger subset of patients who may be in the early phases of the disease.
Estrogen has been investigated in the management of depression. Depression risk increases in women who are perimenopausal. One trial examined the efficacy of transdermal estradiol plus intermittent micronized progesterone in preventing depressive symptom onset among euthymic perimenopausal and early postmenopausal women. Patients (n=172) were randomized to receive transdermal estradiol 100 mcg plus progesterone 200 mg/day for 12 days or placebo plus progesterone every 3 months for 12 months. The study found that patients in the treatment group (17.3%) were less likely to score a 16 on the Center for Epidemiological Studies – Depression Scale (CES-D) in comparison to placebo (32.3%) which would indicate a diagnosis of depression (p=0.03).28 This was one of the first studies to look at long-term effects of prophylactic mood benefits of transdermal estrogen and progesterone alone in women during menopause transition and early postmenopausal period.
Other agents used in psychiatric disorders that are mechanistically involved with estrogen are raloxifene and tamoxifen. Both are selective estrogen receptor modulators (SERM) that are used to treat hormone-sensitive breast cancer. Recently, they have been studied as a potential treatment option for schizophrenia and bipolar disorder. There have been some studies that show estrogen’s potential in a protective role in the pathophysiology of schizophrenia due to lowering psychotic and negative symptoms in pre-menopausal women.27,28 A systematic review of nine randomized controlled trials of raloxifene versus placebo for the treatment of schizophrenia in 561 patients showed improvement in total symptom severity (p=0.009), and a reduction in positive (p=0.02) and negative symptoms (p=0.02). Dosing ranged from 60 to 120 mg per day.29
Tamoxifen’s efficacy in bipolar disorder is thought to result from inhibition of protein kinase C (PKC). Studies suggest that excessive PKC activation leads to disruption of the prefrontal cortex in regulating thinking and behavior. A systematic review of five randomized, placebo-controlled trials evaluated tamoxifen as monotherapy or as augmentation therapy with lithium or valproate in the treatment of acute mania in bipolar patients. The results found that tamoxifen had improved mania scale score compared to placebo.30 Although, these results are promising it does not provide information of the effect of tamoxifen with other agents such as antipsychotics.
Dysfunction of the hypothalamic-pituitary-adrenal axis (HPA) is thought to affect psychiatric disorders such as depression and anxiety due to its release of cortisol. In the STAR*D trials, one of the studies compared the effectiveness of lithium to triiodothyronine (T3) augmentation in patients with major depressive disorder. Patients were augmented with T3 up to 50 mcg/day for up to 14 weeks. Remission rates were greater in the T3 group compared to the lithium group (24.7% vs 15.9%, p=0.4258). The difference between groups was not statistically significant.31 As a result, T3 augmentation is recommended by the American Psychiatric Association (APA) in the 2010 Major Depressive Disorder treatment guidelines.
The CANMAT/IBSD guidelines recommend levothyroxine as a third-line option for treatment of acute bipolar I depression.32 In a 6-week, double-blind, randomized, placebo-controlled trial of supratherapeutic levothyroxine (300 mcg/day) dose as augmentation in 62 patients the mean decrease of HAM-D score was greater in the levothyroxine group compared to the placebo group (-5.1 vs -7.8; p=0.198).33 However, the study failed to show statistical significance between the two groups. The trial used the maximum dosing of levothyroxine, which can cause symptoms of hyperthyroidism including nervousness, hair loss, tachycardia, tremors, and fatigue.
(Click Tables below to view full-size images.)
Future Treatments in Psychiatric Disorders and Conclusion
With the limitations of therapies available to treat psychiatric disorders, clinicians are finding value in other medications that may not typically be used in psychiatric disorders. There is an abundance of data to support possible use of some of these agents, but further studies with larger sample sizes are needed for many of the medications. The efficacy of these alternative therapies has given new insight into the pathophysiology of psychiatric disorders through their mechanisms of actions. This has created the opportunity for new therapies to be developed such as esketamine. In addition, clinicians may have available medications to treat psychiatric disorders not previously treatable as our understanding of these conditions expands
The use of non-psychiatric medications in psychiatric disorders provides us a greater understanding about the pathophysiology as well as another option in treating disease states. Overall, many of the trials had small sample sizes and were used primarily as adjunctive therapy. Before considering these treatment options, ensure that patients have adequate trials of psychiatric medications.
By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
As we push for provider status and other new possibilities, let’s focus on actually doing the things that we are already allowed to do!
It is good that we are not satisfied with the status quo because that fuels us to continue to create new possibilities. It reminds us that our patients need the services that we can provide, so we need to keep pushing for the ability to provide them. However, as we knock on the doors of new possibilities we may be missing out on the possibilities already available to us!
Thinking Inside the Box
While we need to keep thinking outside the box, let’s put some creativity into making our current box work as well as it can. In other words, let’s make the best of the current circumstances. We in pharmacy often let the perfect become the enemy of the good. If we will instead push into some of these innovative practices that are currently options for us, we may find that it helps us make more rapid progress in the future. You will have real life examples of patients you have helped to strengthen your business case. You will have specific barriers you have encountered that we can advocate to eliminate. You will have built the infrastructure and expertise to capitalize on new opportunities as they are developed.
Interested? Here are 4 ideas of areas to explore with your team and your leaders.
Yes, it is complicated. No, the payment structure does not provide your organization with easy money. But we really can serve our physicians and nurses on our teams by providing our medication expertise to patients who need the access. If you get something going you will be able to find that there really are some opportunities for reimbursement. You can start building your team, building relationships, and making a difference in patients’ lives.
The information is changing by the day, but a couple things are clear: A lot of patients will need to be vaccinated, and pharmacy can help. Did you know that pharmacists, interns, and technicians are authorized to administer the vaccine? Tune in to webinars, get trained, and talk with your team about how you can support the testing and vaccination efforts.
Reducing Waste and Patient Costs
Fixing the problems with waste disposal and the cost of healthcare is far above our pay grades. However, did you know that if a patient is on an inhaler or other multiuse item in your hospital, it is legal for you to send it home with them at discharge? An authorized practitioner must order it, and written instructions for use must be sent with the patient at the time of discharge. This is a great way to reduce your waste and helping a patient at the same time.
How do you utilize your staff to perform basic quality assurance activities in the pharmacy? Ask yourself, “Does this job actually require a pharmacist? Could a technician check this process?” Of course there must be a strong process in place, and of course the pharmacist and the managers must verify that everything is being done safely. But too often we limit our technicians just because that’s the way it’s always been done. Check out the Tech Check Tech best practices document on the MSHP website for information about this program.
Not Easy – But a Great Start
Brainstorm about these areas with your team. Do you have questions? Never hesitate to reach out to us for clarification. We may not know the answer, but we can point you in the right direction. If we creatively tackle current problems and current opportunities, we will be ready to take on more responsibility and more opportunities in the future. To paraphrase, we need to be faithful with what we have if we want to be entrusted with more. Start looking in to these opportunities to see what you can accomplish in your world, today.
Don’t Miss What the Public Policy Committee Has Done!
Advocacy 101 Webinar:
Public Policy Updates:
By: Zachary Moszczenski, PharmD; PGY1 Pharmacy Resident (2019-2020)
Mentor: Jackie A. Harris, PharmD, BCPS, Christian Hospital – St. Louis, MO
The use of anti-psychotics to treat delirium has been a controversial topic in recent years, owing to the short supply of high-quality trials and a shift in guideline recommendations. However, the debate started earlier in the beginning of the millennium when we began to ask ourselves: does what we’ve simply been doing for years actually work?
Anti-psychotics certainly made logical sense, as the symptoms of delirium largely mimic psychoses and other symptoms associated with cognitive disorders such as schizophrenia, and non-controlled studies along with expert opinion supported their use. We certainly wanted and felt the obligation to do something about delirium, as it not only can cause significant distress to the patient, family, and caregivers but also is associated with detrimental outcomes, as we’ll discuss. The difference/problem of anti-psychotic use for delirium is that it’s the result of a non-cognitive cause, whether it be a disease state, medication(s), severity of illness, and other factors. Additionally, the course and resolution of the delirium is heavily related to the presence or resolution/absence of the causative factor. Delirium can also be quite subjective in its presentation and assessment (it’s not as easy to assess as blood pressure!).
Since there were not any trials that directly compared anti-psychotics to placebo, the above-mentioned question was starting to and continues to be asked: is treating these patients with anti-psychotics actually doing anything? We’ll address that question in this review of the literature, while also giving an overview of delirium.
What is Delirium?
Before we dive into the available data, it’s important to understand exactly what delirium is and how it can present differently. According to the DSM-V, delirium is a state of attentional, cognitive, and emotional disturbances with or without psychomotor hyper and/or hypo activity.1 It occurs outside of a coma/significantly reduced state of arousal, which may seem like common sense, but it is an important distinction. Disturbances cannot be evident if a patient is too sedated or comatose to show hardly any function at all. This becomes relevant if we overly sedate a patient. They’re technically no longer showing signs of delirium, but we now have another problem on our hands and most likely just not able to tell if we’ve gotten rid of the delirium. The delirious state also differs from baseline mentation/behavior, develops over hours/days, fluctuates throughout the day, and as mentioned above, is not due to another cognitive disorder. There also has to be at least some evidence of another offending medical state or substance, which is essentially never an issue with our critically-ill ICU patients. A higher severity of illness is strongly related to the incidence of delirium, but the copious amount of delirium-inducing agents (opioids, benzodiazepines, steroids, etc.) that these patients commonly receive likely play a larger role.2,3 Simply laying in a bed in the same room for days to weeks at a time certainly doesn’t help either (which is something society as a whole started to understand while on quarantine during the COVID-19 epidemic).
It is also important to distinguish the different types of delirium, as we’ll see, which are described in Table 1.
The hyperactive subtype is easier to identify, though when we screen correctly, it’s easy to see how hypoactive could be more commonly diagnosed.2 SSD is not quite considered clinical delirium and is often not distinguished in comparative trials, though it has been linked with undesirable outcomes in the literature.4
The Problem with Delirium
Depending on the estimate, which is related to how well and often an institution screens for delirium, the prevalence in the ICU can range from 16% to 80% of patients.2 The older and sicker the patient, the higher the risk of delirium, which also tends to exhibit within 48 hours of ICU admission.5 Delirium is also touted to cost the US healthcare system up to an estimated $16 billion annually,2 largely due to the complications associated with delirium listed in Table 2.
Due to these significant complications, it is important to appropriately screen for and diagnose delirium. There are currently two bedside scales recommended by the 2018 Society of Critical Care Medicine (SCCM) Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) guidelines for diagnosing delirium.3 The first and most commonly used scale in the US is the Confusion Assessment Method for the ICU, or the CAM-ICU (Table 3).
This is cousin to the Intensive Care Delirium Screening Checklist, or ICDSC, which is relatively more popular in Canada and other countries. The presence of 4 or more of the symptoms listed in Table 4 will get you a positive diagnosis of delirium.7
Note the differences. The CAM-ICU is potentially more convenient, while the ICDSC is perhaps more useful in distinguishing between hyperactive and hypoactive delirium on its own. Both scales rely on the Richmond Agitation and Sedation Scale (RASS) to measure level of consciousness, ranging from -5 (unresponsive) to +4 (combative). The RASS can be combined with the CAM-ICU to differentiate hyper and hypoactive delirium. It is important to note that both only screen for the presence of delirium, as a higher score does not indicate severity or worse prognosis. Once again, both are recommended for use, with neither one preferred over the other.3
First, we start with our non-pharm methods for managing delirium, which have shown the most positive data and are subsequently the only interventions recommended for the treatment of delirium by the PADIS guidelines.3 These methods are also recommended for the prevention of delirium, though the focus of this review is on treatment only. “ABCDE” is the acronym describing the non-pharm bundle of strategies used in the guidelines, and the components are listed in Table 5. There are various methods used to meet this bundle of interventions, such as sedation vacations, proper sleep hygiene, cognitive stimulation, music, using hearing aids and glasses, etc., but the goal is to address all of them if possible.3
Aside from anti-psychotics, many other agents and classes of agents have been trialed for the treatment of delirium, such as statins, acetylcholinesterase-inhibitors, and ketamine due to their mechanisms of action and theorized pathophysiology of delirium, but none have had great success or are recommended.3 The possible exception is dexmedetomidine, which can be useful for delirium when trying to wean sedation, and it actually is recommended by the PADIS guidelines specifically for agitation preventing extubation (not for routine/general use for delirium).3 The focus then shifts back to anti-psychotics where the main controversy lies, as no agent is FDA-approved for the treatment of delirium. As stated earlier, this controversy was ramped-up by a change in the SCCM guidelines in 2018 not recommending their routine use, which is summarized in Figure 1.
There is an important caveat that is often overlooked, as the 2018 edition also states that “patients who experience significant distress secondary to symptoms of a delirium such as anxiety, fearfulness, hallucinations, or delusions, or who are agitated and may be physically harmful to themselves or others, may benefit from a short-term course of haloperidol or an atypical anti-psychotic”.3 That description paints a picture of hyperactive delirium, and so that is why it is important to distinguish the subtype when determining whether or not a patient would potentially benefit from therapy.
The reasoning behind the recommendation in Figure 1 is that the lack of proven benefit is out-weighed by the potential risk of harm/side effects. So then, the first question is one of efficacy, which can only properly be answered by looking at the available randomized controlled trials (not trials of other anti-psychotics vs. haloperidol). The PADIS guidelines cite four such trials behind their reasoning, and so we’ll combine those (with the one exception of a trial comparing olanzapine to haloperidol from 2004)9 with other available controlled trials to evaluate the efficacy of anti-psychotics for the treatment of delirium.
Randomized Controlled Trials for Anti-Psychotics
The first controlled trial was in 2010, and it is known as the MIND-ICU study.10 It was primarily designed to test the feasibility of a placebo-controlled trial answering this question, which in fairness, is not so easy given the population, setting, ethical considerations, and the subjective nature of delirium. It also set out to see if anti-psychotics, haloperidol or ziprasidone, had a positive effect on days alive without delirium or coma in mechanically ventilated surgical and medical ICU patients. Patients received either haloperidol 5 mg (n=35), ziprasidone 40 mg (n=30), or placebo (n=36) every 6 hours for up to 14 days. Patients were also allowed as needed haloperidol based on provider discretion. No significant differences were found across the above primary outcome (p=0.66) or secondary outcomes, including mortality, ventilator-free days, length of stay, and others. Thus, this is chalked-up as a study against anti-psychotic use, though the trial had notable limitations, with one being an issue of power/actual sample size. Less than half of the patients had an actual diagnosis of delirium based on the CAM-ICU (delirium diagnosis was not required for inclusion). Non-pharm strategies discussed above were not documented as well.
The next trial is also from 2010 and evaluated quetiapine for the treatment of delirium in the ICU.11 The primary outcome was time to first resolution of delirium, and secondary outcomes included time spent in delirium along with the secondary outcomes listed above for the MIND-ICU trial that are common in all of the trials mentioned here. Patients received quetiapine (n=18) 50 mg every 12 hours, titrated to a max of 200 mg per dose per provider discretion, or placebo (n=18) for a max of 10 days. Patients were also allowed to receive open-label as needed anti-psychotics (an order for as needed haloperidol was an inclusion criterion). The treatment group did exhibit a significantly shorter time to resolution compared to placebo (1 vs. 4.5 days, p=0.001) and patients spent less total and percentage of time spent in delirium (36 vs 120 hrs, p=0.006; 53% vs. 69%, p=0.02). This, as we’ll see, is a rare positive result, though the use of as needed haloperidol, the same lack of documentation of non-pharm strategies, and the very small sample size limit the conclusions we could draw about quetiapine.
The HOPE-ICU trial in 2013 was the next hopeful study to try its luck at this question.12 It’s objective was to see if haloperidol had an effect on delirium and coma-free days alive in the first 14 days of ICU admission. Patients were included if they were mechanically ventilated within the first 72 hours, but as with the MIND-ICU trial, baseline diagnosis of delirium was not required. Thus, this borders on evaluating prevention rather than treatment, but it is one of the studies cited by the PADIS guidelines against treatment. Our purely treatment population is likely somewhere within the total study population as well. Patients received IV haloperidol (n=71) 2.5 mg or placebo (n=70) every 8 hours for a max of 14 days, with doses being decreased (but not increased) per provider discretion. Once again, open-label haloperidol was allowed. There was not a significant difference in the primary outcome (p=0.53), though fewer patients in the haloperidol group exhibited agitation (13% vs. 18%, p=0.0075). Also, more patients in the placebo group received open-label haloperidol (8 vs. 18, 95% CI: 0.20-0.94). This was another strike against anti-psychotics with a larger sample size relative to its predecessors, though it was not without its limitations including the afore-mentioned question of prevention vs. treatment, the potential under-dosing of haloperidol, and the common limitations of the previous trials.
Flowing further through time brings us a study in 2015 by Michaud et al. looking at quetiapine again and its effect on the duration of hypoactive delirium in ICU patients.13 This is the one study included that was retrospective; patients were matched with a historical control. Hypoactive delirium was defined as a positive CAM-ICU and a RASS score of 0 to-3. 52 patients that received quetiapine during their ICU stay were matched with 61 patients without any pharmacologic treatment for delirium. The dosing regimen was not provided. The mean duration of delirium was found to be significantly shorter in the quetiapine group (1.5 vs. 2.0 days, p=0.04). Additionally, in the treatment group, if quetiapine was administered within 24 hours of delirium diagnosis, patients spent less time in delirium (1 vs. 3.5 days, p<0.001) and exhibited less time to extubation (1.5 vs. 5 days, p=0.003). This is a potential positive finding for the real population in question (hypoactive), and patients were excluded if they received any other pharmacologic treatment for delirium (no as needed haloperidol). However, the retrospective nature, small-sample size, and lack of a dosing protocol make this more hypothesis generating rather than definitive evidence for the efficacy of quetiapine.
The last and most recent randomized trial is the MIND-USA trial from 2018.14 This highly anticipated study was published after the 2018 update to the PADIS guidelines, and so we can use it to supplement their recommendations. Similar to the MIND-ICU study, it also evaluated the effect of haloperidol and ziprasidone on delirium and coma-free days alive. Patients received either IV haloperidol 2.5 mg (n=192), IV ziprasidone 5 mg (n=190), or placebo (n=184) every 12 hours for a max of 14 days. Doses were titrated per provider discretion up to 20 mg daily for haloperidol and 40 mg daily for ziprasidone, while patients greater than 70 years old received half of the initial and max dose. In keeping with the other trials for haloperidol, no significant differences were seen for any of the primary (p=0.26) or secondary outcomes. Regarding study design, this likely the strongest trial available, due to its larger sample size, standardization and documentation of ABCDE non-pharm interventions, and more practical dose titration strategies. It is not without limitations, though. Open-label as needed anti-psychotics were also allowed, and if you’re scratching your head at IV ziprasidone, you’re not alone (approved for PO and IM use). The investigators needed IND approval from the FDA for this route of administration, and the determination that IV Ziprasidone is half as potent as IV haloperidol is certainly debatable.
A table summarizing the findings of the above trials is located in the Appendix for your reference. Based on these results, coupled with the guideline recommendations, it would appear quality evidence is lacking that supports the use of anti-psychotics. Regarding haloperidol, this notion is further supported by a meta-analysis in 2019 which showed no benefit for any our adverse clinical outcomes.15 Use of quetiapine remains quite popular due to the 2013 PADIS guideline recommendation for atypicals based on the above positive data for quetiapine. Any time spent in delirium can be more than a hindrance to all involved, and so the possibility of reducing delirium even by just half a day can be attractive. Its use for delirium refractory to non-pharm interventions may be reasonable based on the above studies, especially if dosed at night time if the patient is having sleep/wake cycle disturbances, though the available evidence just isn’t quite strong enough to fully recommend the routine use of quetiapine.
The Problem with Anti-Psychotics
We’ve answered (or at least addressed) the question of efficacy, and so the question of safety or potential harm remains. Anti-psychotics are by no means benign, and some common adverse effects are listed in Table 6. This list is by no means exhaustive, and some agents are associated with greater frequencies or cause more serious adverse effects than others.
Some of these effects are more associated with long-term use, and so we typically wouldn’t be concerned with short-term treatment for delirium. However, one institution estimated that nearly half of their anti-psychotic naïve ICU patients received anti-psychotics, and 24% of them were prescribed at discharge.17 These results are similar in other studies,18 and while inappropriate continuation can and should be addressed by more systematic interventions, long-term effects could still be considered when initiating therapy.
QTc prolongation can happen in the short-term and is a common concern, especially in our critically-ill cardiac patients. What’s interesting is that in all of the trials discussed above, no differences in QTc prolongation, or any adverse effects for that matter, were seen compared to placebo. A retrospective chart review in 2018 replicated these results with quetiapine, showing a mean baseline increase of just 2 msec in patients that received quetiapine for delirium.19 So, while it is certainly possible, QTc prolongation may not be as much of a concern as previously thought, especially for quetiapine. However, another previously non-associated adverse event may exist for quetiapine use in ICU patients. Recently, the concern for pulmonary complications has arisen for short-term use, with one retrospective review showing an increase in these complications for critically injured trauma patients that received quetiapine for delirium, which included respiratory failure and aspiration, bacterial and ventilator-associated pneumonia.20
Conclusions and Future Directions
The incidence of delirium in critically-ill patients is associated with significant morbidity and mortality. What is not always focused-on is the serious short and long-term psychological toll this disease state can have on patients, families, and caregivers, and so we should and have taken measures to combat this issue. Patients in the ICU should be routinely screened using guideline-recommended tools, especially if they are at higher risk, such as the elderly, more severely-ill, and patients receiving medications associated with the induction of delirium.3 We can use proven and recommended non-pharm interventions (the ABCDE bundle) to prevent and treat delirium, though when this fails, we often turn to anti-psychotics to mitigate the above complications. However, as we’ve seen, there is an absence of quality data supporting the efficacy of anti-psychotics for delirium, while the actual risks of short-term use are not as evident as once thought and are still under debate.
There may still be hope for the future, though. Haloperidol has failed to show any benefit, but does that mean all anti-psychotics won’t? Unlike other classes of medications, these agents can vary widely in their receptor profiles in affinity and activity, and so the failure of one does not necessarily rule-out the efficacy of another. Two controlled trials discussed above have shown a potential benefit with quetiapine, and while the results may not be strong enough to recommend the routine use of quetiapine, they are certainly promising. As it so happens, a clinical trial, aptly named the HALOQUET trial, evaluating quetiapine or haloperidol against placebo is ongoing in Canada (NCT01811459, ClinicalTrials.gov), and so this study and further research can help us better evaluate this agent. Other agents could potentially be evaluated as well. For example, cariprazine is a newer anti-psychotic that has shown benefit for the treatment of negative symptoms of schizophrenia (cognition, disorganized thoughts, blunted affect, etc.), which largely mimic symptoms of hypoactive delirium.21 While investigation of this agent for delirium is currently unlikely due to cariprazine still being brand name (VraylarÒ) and therefore expensive, it’s possible this and similar agents could be evaluated or developed in the future. Once again, the main issue is the lack of large controlled trials, and so further quality research will be the only remedy to the practitioner’s own delirium regarding this debate.
By: Brooke Jacobson and Kyle Roof, PharmD Candidates 2021; UMKC School of Pharmacy
Mentor: Ekeni Livingston, PharmD, BCPPS; Children’s Mercy Kansas City
Managing patients in the pediatric intensive care unit (PICU) has evolved immensely over the years. While striving to successfully treat the patient’s underlying conditions, providers have often encountered consequences from their own interventions. The goals of caring for critically ill patients not only entails preventing mortality but also avoiding complications associated with prolonged stays in the PICU.1 Delirium is a common consequence addressed in the adult intensive care unit (ICU) population. Conversely, delirium in the pediatric population is often not addressed and rarely studied. The Diagnostic and Statistical Manual of Mental Disorders: Fifth Edition (DSM-5) characterizes delirium as an acute onset of fluctuating disturbances of consciousness, attention, cognition, and perception.2 According to multiple studies, delirium is associated with higher rates of increased hospital length of stay, long-term cognitive impairment, increased time on mechanical ventilation and mortality.1,3
Multiple proposed mechanisms exist to explain the manifestation of delirium in critically ill patients. The first mechanism is the predisposition of patient-related factors (e.g. age, genetics, underlying diseases) and the second is precipitating factors.1 Some examples of precipitating factors can include medications, metabolic dysfunction, progression of disease, and the stressful environment that is associated with a PICU stay.4 Prolonged use of sedatives and analgesics are often the predominant medications that contribute to delirium in the PICU. There are a few processes thought to contribute to delirium in the pediatric population.
The first process proposes an alteration in the blood-brain barrier’s (BBB) permeability secondary to a high prevalence of systemic inflammation.1,4 This leads to an increased production of cytokines and the transport of cytokines across the BBB resulting in ischemia and the destruction of neurons.1,4 The second hypothesis suggests an alteration of neurotransmitter regulation. Decreased levels of acetylcholine and increased levels of dopamine are likely the main contribution to delirium, however, the dysregulation of norepinephrine, serotonin, melatonin, gamma amino-butyric acid (GABA), histamine, and glutamate are also thought to play a role in the process.1,4 The last proposed hypothesis suggests a production of reactive oxygen species as a result of hypoxia and increased cerebral metabolism.1,4 Multiple studies have demonstrated that hypoxia in the intraoperative setting is associated with a reduction in cognitive function.1 The above proposed hypotheses give insight as to how delirium manifests in the pediatric population and can help determine possible treatment options.
Presentation and Screening
There are three main subtypes used to classify delirium in the PICU based on the patient’s presenting behaviors.5 Patients can be classified as hypoactive, hyperactive, or mixed-type delirium depending on the presence or absence of dopamine.5 Hypoactive delirium, the most common form, results from a significant deficiency of dopamine and is demonstrated in patients through a depressed level of consciousness and withdrawal from their environment.5 Unfortunately, hypoactive delirium rarely raises concern within the medical team and patients are often incorrectly categorized as non-delirious. Hyperactive delirium results from an excess of dopamine and triggers agitation, restlessness, emotional instability, and psychosis.5 Mixed-type delirium consists of the fluctuation between hypoactive and hyperactive states.5
Several tools have been created to assess delirium in PICU patients. One of the earlier tools created was the Pediatric Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU). This tool assesses the clinical features of altered mental status, inattention, altered level of consciousness, and disorganized thinking.6 There are multiple limitations associated with the pCAM-ICU including but not limited to: requirement of patient cooperation, extensive nurse training, limitations in patients with developmental delay, and restricted use to children greater than 5-years-old.7 Another tool designed for the assessment of pediatric delirium is the Pediatric Anesthesia Emergence Delirium (PAED) screen.7 This screening tool only detects the hyperactive subtype of delirium which entails obvious limitations. Lastly, the Cornell Assessment of Pediatric Delirium (CAPD) screening tool is an adaptation of PAED. CAPD is a more ideal screening tool due to its additional components that allow detection of all three subtypes of delirium.6,7 Table 1 demonstrates the CAPD screening tool. Elements 7 and 8 allow the detection of both hypoactive and mixed-type delirium. Using this tool, a collective score of 9 or above indicates detection of delirium. Table 2 is included below to characterize the normal behavior of a developing child in the PICU environment.7
Risk factors for developing pediatric delirium include younger age, male gender, preexisting cognitive impairment, development delay, previous delirium, positive family history of delirium, and preexisting emotional and behavioral problems.4 While these factors are not adjustable, there are other non-pharmacological interventions that can help prevent and treat pediatric delirium. Environmental factors such as physical restraints, high noise levels, poor lighting, frequent staff changes, and disease entities may exacerbate delirium and are often associated with high mortality risk.4 Environmental interventions may be sufficient to manage pediatric delirium without the use of medications. These strategies include repeated reorientation by family or familiar nurse, calendars and clocks, pictures of family, familiar toys from home, maintaining bright light during the day and dimming light at night, keeping a regular routine, and minimizing noise levels.4 These strategies help decrease confusion and fear and ultimately decrease the risk and prevalence of delirium.
Delirium is most often related to the use of pain and sedation medications. This can include benzodiazepines, opioids, propofol, barbiturates, and ketamine.6 Utilization of these medications is often necessary as they are crucial for the comfort and care of the patient. However, reducing the dose of these medications whenever possible and using pain and sedation scoring tools [e.g. Faces, Legs, Activity, Cry and Consolidation (FLACC) tool and Richmond Agitation Sedation Scale (RASS)] to obtain an appropriate pain and sedation level is imperative.7 Daily sedation interruption or a “sedation holiday,” is an important element of PICU management. These interruptions not only reduce opioid and sedative exposure, but also orients the patient to time and place which can reduce delirium and delirium-associated complications.
The disruption of the sleep-wake cycle and alterations of sleep stages are prevalent in delirium.6 Benzodiazepines affect both the slow-wave and non-REM sleep.6 This might explain the mechanism by which this drug class causes delirium. Although an effective sedative class, multiple studies render benzodiazepines a high-risk medication for delirium and should carry limited use in critically ill patients and avoided in patients experiencing delirium. Because the circadian rhythm appears to be disrupted with high sedation and in the presence of delirium,4 this introduces a theory that melatonin may be reduced in critically ill patients.6 Kain et al,8 a randomized placebo-controlled double-blind trial, is a small study (n=140) that compared midazolam with melatonin for pre-operative anxiety (primary outcome), compliance with induction, emergence behavior, and parental anxiety (secondary outcomes). The study compared melatonin 0.05 mg/kg, 0.2 mg/kg, 0.4 mg/kg (max 20mg), and midazolam 0.5 mg/kg. Although midazolam demonstrated greater reduction in preoperative anxiety (p < 0.001), patients who received melatonin at higher doses demonstrated less emergence delirium than those who received midazolam (p < 0.05). It should be noted that this study only assessed short-term use of melatonin for emergence delirium. However, there might be a role for melatonin in the prevention of delirium in the PICU, but further studies are needed to make this claim.
The alpha-2 adrenergic agonists, dexmedetomidine and clonidine, are useful anxiolytic and sedative agents utilized in the pediatric population.6 These agents carry minimal risk for respiratory depression and have a decreased amnestic effects reducing the risk for delirium.6 Although dexmedetomidine is the only agent of the two that are approved for pediatric sedation, they are both widely used.6 Dexmedetomidine decreases the need for benzodiazepines, blunts the sympathetic stress response and catecholamine release, and may reduce the need for other sedatives.4 However, prolonged use of these agents can cause significant hemodynamic instability. Dexmedetomidine can be transitioned to clonidine for a continued, long-term alpha-2 agonist effect.4
Important aspects for the management of delirium are identifying the underlying cause and treating patients early. Delirium is typically multifactorial, and it is important to resolve the underlying cause while also avoiding agents that may worsen delirium. Most often, delirium will improve with management of the underlying illness, minimizing triggers, and optimizing the patient’s environment.1 However, if delirium persists, pharmacologic therapies should be used. As previously mentioned, one hypothesized delirium mechanism suggests that excessive dopamine and deficiency of acetylcholine contributes to delirium.9 As a result, antipsychotics, specifically atypical antipsychotics, are most often used for treatment. They relieve agitation, perceptual disturbance, sleep-wake cycle abnormalities, and behavioral abnormalities. In comparison with the earlier generations of antipsychotics, atypical antipsychotics have less extrapyramidal side effects and drug interactions.9 Antipsychotic therapy is used off-label as they are not approved by the Food and Drug Administration for treatment of delirium in adults or children.9
In a recent retrospective matched cohort study, the University of Maryland Children’s Hospital compared the use of antipsychotics versus no pharmacological interventions for the treatment of delirium in critically ill children.9 The most common antipsychotic drugs that were used were haloperidol, risperidone, and quetiapine. This study demonstrated that patients treated with antipsychotics had more delirium days (6 vs. 3, p=0.022), longer mechanical ventilation days (14 vs. 7, p=0.017), and longer PICU stay (34 vs. 16 days, p=0.029). However, although no significant differences were found, more patients requiring pharmacological treatment for delirium had previously been medicated with benzodiazepines (2 vs. 12), opioids (3 vs. 13), and dexmedetomidine (2 vs. 13) than with the untreated group.9 It is also important to note that the sample size for the study was 15 patients, and only 8 of 15 patients were treated on day 2 of diagnosed delirium.
Haloperidol, although a first generation antipsychotic, is frequently used in the adult population to treat hyperactive delirium in the ICU.5 Haloperidol is a dopamine antagonist that exerts its action in the brain to reduce hallucinations, anxiety, sedation, and restore attention.5 It has few anticholinergic and hypotensive side effects and is less sedating than other agents. However, due to its significant extrapyramidal and cardiac adverse effects it has been generally replaced by atypical antipsychotics with similar efficacy.6 Haloperidol is an option for patients with hyperactive delirium and/or requiring intravenous (IV) medication administration.9
Atypical antipsychotics such as risperidone, olanzapine, ziprasidone, and quetiapine are the most commonly used atypical antipsychotics in critically ill patients with delirium.5 This class of medication not only blocks dopamine, but also significantly blocks serotonin, norepinephrine, and acetylcholine.5 Due to the activity on additional receptors, they are generally more sedating and may cause tachycardia, hypotension, lower seizure threshold, and weight gain. Tukel SB, et al,10 compared the effectiveness and safety of olanzapine, risperidone, and quetiapine in pediatric patients with delirium. This was a retrospective descriptive study of 110 patients that concluded the following: the final Delirium Rating Scale-Revised-98 scores in pharmacologically treated patients were significantly lower than the original scores at diagnosis (p<0.001).10 The authors concluded that higher doses were needed when delirium was drug-induced. No significant adverse effects occurred.10 Although this study had many limitations, it is important to note that there were no differences between the effectiveness of antipsychotics, and no significant side effects were discovered in the study. Because side effects are still a concern, it is suggested to use antipsychotics for the shortest duration and smallest dose necessary in order to avoid unwanted side effects.10 Information about each medication is indicated in Table 3.
Delirium can cause severe and irreversible cognitive impairments if not appropriately addressed and managed. Although there is limited literature available, it is a rising area of concern due to its increasing incidence and poor outcomes. The morbidity of delirium may manifest as post-traumatic stress, depression, anxiety, and permanent changes in cognitive function.6 Despite high prevalence rates and concern for delirium, hesitation remains to embrace pharmacological therapy due to uncertainty of clinical diagnosis and lack of clear treatment options within available literature. This provides a clear need for additional studies for the treatment of delirium in critically ill pediatric patients.
By: Kathryn Renken, PharmD Candidate 2021 and Morgan Luttschwager Rose, PharmD Candidate 2022; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Amanda Grapperhaus, PharmD, BCPS; SSM Health DePaul Hospital
According to the Centers for Disease Control and Prevention, of children age 3 to 17 years old in the United States, 7.1% have diagnosed anxiety and 3.2% have diagnosed depression. Following diagnosis, 78.1% of the children with depression and 59.3% of the children with anxiety received treatment.1 In adults, first-line treatment for both anxiety and depression is antidepressant medication from the drug class of selective serotonin reuptake inhibitors (SSRIs).2 In children, these drugs are often less helpful. When used in pediatric patients, antidepressants can cause a state of hyperarousal known as activation, which can cause an increase in activity, impulsivity, disinhibition, restlessness and insomnia.3 These symptoms typically occur following antidepressant initiation or dose changes, and they can be harmful. In a placebo-controlled study of fluoxetine, an SSRI, five out of seven pediatric patients experiencing these symptoms discontinued their medication as a direct result of these symptoms.4
The pathophysiology of antidepressant-induced activation is not fully understood, but there are many hypotheses that predict its pathway. Some predict that it is a variant of the manic phase of bipolar disorder, which is supported by the fact that patients with a family history of bipolar disorder are often more susceptible to experiencing activation. Others believe that some individuals are inherently more sensitive to the increased serotonergic tone in areas of the brain that regulate arousal that follows SSRI use, which can manifest itself as the classic symptoms of activation.3 No matter the source, pediatric antidepressant-induced activation is a serious problem in treatment of children with depression and anxiety.
Prevention of Activation
Some patients have a higher risk of antidepressant-induced activation based on factors including age, cytochrome P450 (CYP) polymorphism, and primary disorders, which cannot be changed. In addition, an individual's drug metabolism can lead to changes in bioavailability, drug concentration, and cumulative drug exposure, which also influences activation. There is an increased risk of activation in patients with the poor metabolizer polymorphism of CYP2D6 when CYP2D6 metabolizes the drug as it can cause a higher serum concentration of the drug. Increased activation with SSRIs can also occur when there are changes in serotonin transporter expression. For management of activation, use low doses of SSRIs with slow, planned titration to reduce the likelihood of the high rates of serum SSRI concentrations.5 Correct pediatric dosing and titrations can be accessed through the Clinical Practice Guidelines (e.g.: Guidelines for Adolescent Depression in Primary Care). Another way to reduce high serum concentration of SSRIs is to switch from immediate release to extended release, which will allow the drug to be released over a period of time. This will reduce the maximum drug concentration in the blood, reducing the risk of activation. Even with these strategies, activation may occur when increasing patient doses. Research has found that discontinuation of the medication and reinitiating at a lower dose can resolve the adverse effects.6
Currently, two SSRIs and one serotonin-norepinephrine reuptake inhibitor are FDA-approved for the treatment of major depressive disorder and generalized anxiety disorder in children, respectively. Escitalopram is approved for children ages twelve years old and older, while fluoxetine is approved for use in children ages eight years old and older. Duloxetine is approved for children ages seven years old and older. In addition, clomipramine, fluoxetine, fluvoxamine, and sertraline hold FDA indications for obsessive compulsive disorder in children, and an olanzapine with fluoxetine combination drug has an FDA indication for bipolar depression in children.7 These medications are less likely than other antidepressants to cause activation in children, which leads to their official labelled indication for use in children.
Management of Activation
When initiating a child on any antidepressant, it is important to closely monitor for symptoms of activation and to understand what to do if activation occurs. The guidelines recommend either face-to-face or telehealth appointments between the patient and prescriber regularly during initiation and dose changes to ensure that the patient is not getting clinically worse or experiencing adverse effects of the prescribed medication.8 Between appointments, parents should watch for symptoms of activation or suicidality. Researchers at the University of Florida have developed a screening tool for parents, called the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP), to use to monitor their children after starting antidepressant medication. This tool assesses activation across five different areas of symptoms, allowing parents to easily see if their child is displaying these symptoms and if this should be a cause for concern. The TEASAP has been shown to have internal consistency reliability, test-retest stability, concurrent validity, and predictive validity, even when conducted by parents.9
If a child taking antidepressants shows symptoms of activation, it is important to contact the prescriber to let them know about it. After that, there are a few different options for management. One of the most likely proposed causes of activation is a high blood concentration of the drug, so either decreasing the dose or changing to an extended-release rather than immediate-release formulation can help to relieve symptoms. Otherwise, discontinuing the drug and prescribing a new one at a low dose is appropriate; however, if a child shows activation symptoms with one antidepressant, then they are likely to experience these symptoms with other antidepressants.3,10 It is also important to assess medication adherence in children showing activation. Oftentimes, the symptoms of antidepressant withdrawal are similar to the symptoms of activation. Lastly, individual symptoms can be treated with other medications, such as treating insomnia with melatonin.
By: Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
Pharmacists, interns, and technicians are health care leaders - here are two ways that we can make an impact.
5 Minutes to Make an Impact
Do you know how to contact both of your US Senators and your US Representative in one click? If you invest 5 minutes with ASHP you will be able to do just that. The ASHP Action Center is a website where you register to receive updates about pressing legislative issues, making it very simple to send expertly-written form emails at the times when they will have the greatest impact. Click here today - it only takes a few minutes to register yourself and enter your information. Only your email and zip code will be required for future logins.
The Impact of Social Justice
Social Justice is an issue that is so deep and broad that it can feel overwhelming. But for me, the starting point is pretty simple - caring for people. Each of us work for organizations that have 'caring' as part of our core mission. Ours is "Above all else, we are committed to the care and improvement of human life." Each of us work for organizations that have respect as part of our core values. If we each model caring and respectful thoughts, words, and actions, that is a good place to start.
Many of us are in roles where we can also hold others accountable for their words and actions, and we create a culture by what we call people into and what we tolerate. Even if you are not a formal manager, you still can make an impact on your work environment.
I think the next thing we can do is purposefully think how we can serve and build into anyone who is a step or 2 behind us on life's journey. That may be to mentor a student, or to provide a professional development series for technicians and arrange the schedule so that they can attend. It may be to invest in that younger leader who has potential. Or to meet routinely with a technician or intern and provide the type of career guidance that you have received from family, friends, and mentors in your life. It may be to go to bat for your technicians to get them a raise that pays them for the value they provide. In this way we are spreading justice and mercy and care and respect to everyone, and you will certainly help the ones who have been dealt a less favorable hand by life. And it is always helpful to remember the words, "Be kind - everyone you meet is facing a hard battle."
If you are interested in ASHP’s work on this topic, stay tuned to the ASHP Task Force on Racial Diversity, Equity, and Inclusion and reach out to me to get involved with the Public Policy committee.
You Can’t Do Everything, but…
Right now we are all busy with everything that is going on. Focus on these 2 practical ways to make an impact on our world.
Don’t Miss What the Public Policy Committee Has Done!
Advocacy 101 Webinar: This is a 1 hour webinar that gives the basics about advocating for our patients at the legislative level and at the regulatory level. It is a brief tutorial of ‘how things work.’ Link
Public Policy Updates:
January/February: Advocacy: Leadership In Action for Pharmacists and Technicians
o It is our job to understand the current rules so we follow them correctly, and improve the rules, using the systems that are in place.
March/April: Advocacy: A Winning Game Plan, and a Winning Team
o The game plan for advocacy is caring, prioritization, education, and persuasion. The next step is to build our team.
May/June: Legislative, Regulatory, and Associations
o Do you know how change happens? Through the work of elected officials and votes; government employees, inspectors, and boards, and groups of thought leaders, providing best practices and direction for the profession. Legislative, Regulatory, and Associations.
July/August: Regulation in Uncertain Times
o As pharmacists, we have a responsibility to stay knowledgeable and get involved to ensure that our patients get the care that they need. Especially in these uncertain times!
By: Jamie Sullivan and Brooke Jacobson, PharmD Candidates 2021, UMKC School of Pharmacy
Mentor: E. Claire Elson, PharmD, BCPPS; Children’s Mercy Kansas City
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. As a result, abnormal, viscous secretions primarily affect the gastrointestinal and respiratory system in people with CF.1 These secretions cause a complex respiratory triad of increased inflammation, obstruction, and infection that may eventually lead to bronchiectasis, parenchymal destruction, and increased morbidity and mortality.1
While there have been significant advances in therapies to treat the underlying cause of CF over the last decade, a major focus of treatment remains the prevention and treatment of acute and chronic infection in the airways.1 A mainstay of treating airway infections in CF is the utilization of antibiotic therapy. However, because CF individuals have altered airway pathophysiology and require increased treatment, individuals are at risk of resistant infections. A child with CF may develop chronic infections and become colonized with certain organisms such as Staphylococcus aureus and Haemophilus influenzae which eventually causes damage to the lungs.3 Consequently, this allows the introduction of more virulent pathogens such as Pseudomonas aeruginosa, Burkholderia species, Achromobacter, and Stenotrophomonas maltophila to infect the lungs of the individual. Because chronic infection with P. aeruginosa is associated with lung function decline and mortality in CF patients,3 utilization of antimicrobial stewardship in the early stages of CF is imperative for slowing the progression of disease.
In every patient, it is important to practice proper antimicrobial stewardship. Most institutions use an institutional-specific antibiogram to guide antimicrobial empiric therapy. However, this can be difficult in special populations like CF as most institutions do not include CF cultures in their antibiogram. Not having access to a CF-specific antibiogram can lead to inappropriate and improper antibiotic selection and potentially increased rates of resistance. Therefore, Children’s Mercy Kansas City (CMKC) Cystic Fibrosis Center developed a CF-specific antibiogram to guide antimicrobial selection and monitor changes in susceptibility patterns over time.
This was a single center, retrospective, observational study beginning in 2015 and extending to 2026. To conduct this study, approval was obtained from the Institutional Review Board. This report includes a five-year interim data analysis from 2015-2019. The primary objective was to develop a CF-specific antibiogram at CMKC in order to guide empiric antimicrobial selection and treatment. Secondary objectives included a comparison of the institutional antibiogram with the CF-specific antibiogram in order to characterize differences in susceptibilities and changes of susceptibility patterns over time. CF patient culture data collection started in 2015. All CF patient cultures, obtained by sputum or deep pharyngeal swab, obtained at CMKC were included in the CF antibiogram. Patients were identified via a microbiology report. The following data were collected: demographics, microorganism isolated, and susceptibility information. Susceptibility information was reported for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (PA), Achromobacter, Stenotrophomonas maltophila, and Burkholderia species. CMKC hospital-wide (HW) antibiogram and CF-specific antibiogram were compared. Descriptive statistics and Fisher’s exact test for categorical data were utilized for analysis.
At CMKC, the CF-specific antibiogram has been reviewed and published from 2015-2019 in conjunction with the institutional antibiogram. The MSSA, MRSA and PA isolates collected from expectorated sputum or deep pharyngeal swab in the CF population were compared to the CMKC HW antibiogram.
Over the five-year period there was a total of 6864 cultures with MSSA and 3202 cultures with MRSA isolated in both CF and HW antibiograms. Overall, MSSA and MRSA CF isolates were less susceptible compared to HW isolates for every antimicrobial tested. Clindamycin was significantly less susceptible in the CF population compared to the HW population for MSSA (71% vs. 79%, p=0.25) and MRSA (39% vs. 83%, p<0.001). MRSA was found at a higher rate in the HW isolates compared to the CF isolates (33% versus 27.5%). These results are summarized in the table below.
PA was the most prevalent gram-negative isolate seen among CF cultures, with 480 isolates identified over the five-year period. The PA isolates were less susceptible in CF cultures than in the CMKC HW population for every antimicrobial tested. The difference was most significant for aminoglycoside antibiotics in the CF population compared to the HW population for amikacin (71% vs. 99%, p<0.0001), gentamicin (71% vs. 93%, p<0.0001), and tobramycin (87% vs. 97%, p=0.0165). These results are summarized in the table below.
Overall, gram-positive and gram-negative microorganisms isolated from CF cultures were less susceptible when compared to the CMKC hospital-wide antibiogram. Furthermore, there did not appear to be significant changes in susceptibility patterns throughout this five-year interim analysis. At CMKC, the CF-specific antibiogram will continue to be reviewed and published each year with our institutional antibiogram. It will continuously be utilized to guide empiric antibiotic therapy selection for individuals with CF. The development of a CF-specific antibiogram has important clinical implications to guide empiric antimicrobial selection, and its development will allow for monitoring of resistance trends over time.
By: Nirali Ragha and Yostena Khalil, PharmD Candidates 2022; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Nausheen Hasan, PharmD, BCPPS; St. Louis Children’s Hospital
Spinal muscular atrophy, more commonly known as SMA, is a genetic disease. This disease primarily effects muscles; muscles start to get smaller, or atrophy, because nerve cells located in the spinal cord are not stimulating them. This atrophy hinders the patient's ability to eat, walk, or breathe. SMA is characterized by four different categories ranging from type 1 to type 4. The earlier in the age that a baby is diagnosed with SMA, the greater the impact on their motor function. Genetic testing (tests for any
variations in the SMN1 gene) and a muscle biopsy are both methods of diagnosing a pediatric patient with SMA; as of January 2019, SMA is now on the newborn screening for Missouri.1 The most severe type of SMA is type 1, which includes babies diagnosed at birth or in infancy.2 Pediatric patients with type 1 SMA have a life expectancy of fewer than 2 years.2 With the addition of new treatments, the survival rates in pediatric patients have improved tremendously, but at an extraordinary cost. Nusinersen (Spinraza) costs about $708,000 in the first year of treatment and about $354,000 in subsequent years due to it being a long-life therapy.3 Another treatment on the market is onasemnogene abeparvovec (Zolgensma), which retails at about $2.125 million dollars, but insurers have the ability to pay $425,000 a year for five years; however, coverage varies based on patient’s insurance.3
Zolgensma has a targeted approach by selecting the genetic root cause of SMA. It replaces the Survival of Motor Neuron 1 (SMN1) gene that is nonfunctioning. The SMN1 gene constitutes the critical point in making SMN protein, which is essential to the survival of the motor neuron cell.4 If the motor neuron cell is dead, then it will cause the muscles to weaken so that breathing, eating, and moving would become extremely difficult. Zolgensma is made up of a working copy of a human SMN gene. This gene is placed inside a vector.5 The vector then takes the new working human SMN gene to the motor neurons cell body. The vector is made from a particular virus that is known as adeno-associated virus 9 (AAV9).5 This particular vector is not seen as a foreign pathogen, thus our immune system does not attack it. Once the human SMN gene reaches its destination in the motor neurons cell body, it prompts the motor neuron to start producing SMN protein. Since the motor neuron will not be able to produce a sufficient amount of SMN protein, the motor neurons that have not died off will be able to survive.
Spinraza works by penetrating the central nervous system. In order to penetrate the central nervous system, children receive intrathecal injection through a lumbar puncture. Spinraza then uses the spinal fluid to move through the central nervous system. Children with SMA have a difficult time relaying messages from the brain to the motor cells. While taking Spinraza, the spine will act as a tunnel to relay motor messages from the brain to the body in a quicker motion. It contains an antisense oligonucleotide (ASO) which controls the mutations that are present in the affected chromosomes.6 The binding then targets RNA and regulates gene expression. This regulation then has the potential to enhance the functional SMN proteins.5
During phase 3 of a trial for Spinraza, called ENDEAR, there were 121 patients (age ≤ 7 months) with early-onset of SMA who received their first-time dose of Spinraza. The primary endpoint of this trial was to see if Spinraza could decrease the need for permanent ventilation and meeting the criteria for motor milestone responders using HINE-2 compared to patients not receiving treatment at all. The study found that 61% of patients on Spinraza survived without the need for permanent ventilation, compared to patients who were not receiving treatment.7 In addition, 51% of treated patients compared to 0% of untreated patients achieved the motor milestone responder criteria, which are defined by an HINE-2 score at 9 months. Patients on Spinraza achieve full head control, supine to prone rolling, independent sitting, and standing.6 The study also found that over time patients who were treated with Spinraza continued to improve quality of life, compared to patients who were untreated and saw a decline in motor milestones.
In the STR1VE clinical study for Zolgensma, 22 patients with SMA type 1 received a therapeutic dose of Zolgensma at an average mean age of 3.7 months.8 The results of this study showed that 91% of patients who received Zolgensma were alive and did not require any permanent breathing support at the age of 14 and 18 months. The result of patients who were able to sit without any assistance for at least 30 seconds at the age of 18 months was 59%.8 In addition, about 95% of patients achieved a CHOP INTEND score (a scoring system that measures motor function) of at least 40, which has a scale of 0-64 where higher scores indicate better motor function.8
Spinal muscular atrophy is an extremely dangerous genetic disease, and patients who have it have a very low rate of survival. Patients may be placed permanently on ventilators, and their ability to eat and walk may be hindered, as well. Fortunately, Spinraza and Zolgensma can improve both the quality and life span for these patients, but at a great cost. The STRIVE and ENDEAR trials have shown that Zolgensma and Sprinraza are effective for the treatment of SMA. Unfortunately, both these drugs are high-priced, and insurance may not be readily available for everyone.
By: Samira Zantout, PharmD Candidate 2021; UMKC School of Pharmacy
Mentors: Jamie Rouch, PharmD, BCPPS and Jean Freudenthal, PharmD; Children’s Mercy Kansas City
How many vaccines have you received in your lifetime? Following the Centers for Disease Control and Prevention (CDC) recommendations, the average person receives over 30 doses of vaccinations by the age of 18 and that is not counting the annual influenza vaccine.10 Completing and staying up to date on different vaccination series is an investment into building long-term immunity against vaccine-preventable diseases. However, it can be a lengthy time commitment, especially for patients that have to redo their entire vaccination schedules. This is the reality for patients that receive a hematopoietic stem cell transplant (HSCT). 2,4
HSCT is a procedure in which hematopoietic stem cells are harvested from a donor (termed allogeneic) or from the patient (termed autologous) and then transfused intravenously into the patient. Ultimately, the newly transfused cells will travel and reach the bone marrow, where they can completely take over or enhance the functionality of the patient’s bone marrow to produce new blood cells.6 With almost 84,000 stem cell transplants completed worldwide every year, the number of living HSCT recipients is on the rise.8 A growing number of those living recipients are pediatric patients.
The role of HSCT in the pediatric population has widely expanded over the past two decades to go beyond conventional, oncological indications like leukemias and lymphomas.4,5,6 In fact, one-third of pediatric patients undergo HSCT to treat a variety of non-oncological disorders, such as sickle cell anemia, metabolic disorders, and immune deficiencies like beta thalassemia.4,5,6 While the procedure aims to replace defective cell lines and ultimately improve the patient’s impaired immune system, it comes with numerous risks and complications the transplant team must address. For example, serious infections have been shown to account for 4- 20% of late deaths after receiving an HSCT and infections are the leading cause of posttransplant complications.6 Due to the complete dissolution of the recipient’s current immune system and the slow reconstitution process over 1 to 2 years to recover those immune defenses, the risk of developing an infection or contracting communicable diseases is the highest in those first 2 years after the transplant.4,5,6 This is especially true for vaccine-preventable diseases.
HSCT-recipients lose their antibody titers to vaccine-preventable diseases like tetanus, polio, measles, mumps, rubella, and others within months to 10 years post-transplant if they are not revaccinated.2,3,7 Moreover, this gradual loss of immunity is affected and
can be accelerated by several factors, including chemotherapy regimens, immunosuppressive regimens, the type of HSCT, and the source of the received stem cells, among other factors.2,3,7 Previous studies have noted that HSCT recipients have a nearly 50-fold increased incidence of invasive pneumococcal disease compared to the general population, with a case-fatality rate of 10-20%.5 Similarly, studies on influenza infections have noted significant morbidity and mortality rates as high as 15- 17% in HSCT-recipients.5 While this reality impacts HSCT-recipients of all ages, the pediatric population is particularly vulnerable.
Pediatric HSCT recipients may not have completed many of their vaccination series prior to the transplant due to young age or disease-associated morbidity and, as a result, may not have built up any pre-transplant immunity.3,5,6 Combined with post-transplant immunosuppressive regimens that can further diminish vaccine-induced immunity, recent occurrence of vaccine-preventable disease outbreaks, a decline in vaccine coverage among the pediatric population, and the exposure risks that naturally accompany daycare or school entry, pediatric HSCT-recipients are at a significant risk of contracting vaccine-preventable diseases.3,5,6,7 Working proactively to minimize this risk is imperative for this population. The most effective, proactive measure health care providers can take to combat vaccine-preventable diseases is quite simple: revaccination. This is a paramount initiative where pharmacists can lead a phenomenal impact.
While the concept of revaccinating all HSCT-recipients seems simple enough in theory, many HSCT recipients remain unvaccinated, are vaccinated late, or undergo an incomplete schedule of vaccinations after their transplant.1,4,6 The most common reasons for these gaps in care include poor documentation of vaccine administration, loss to follow-up with other providers, and conscious deferral by clinicians.1 HSCT recipients follow a unique vaccination schedule that pharmacists can familiarize themselves with and utilize to identify the optimal timing and the best candidate for each vaccination (see IDSA’s Clinical Practice Guideline for Vaccination of the Immunocompromised Host).9 As pharmacists, we are optimally placed in healthcare institutions and in community settings to identify these vulnerable patients and recommend appropriate vaccinations. We can be their vocal advocates to prevent deviating from the recommended vaccination schedule. Moreover, we can be the safety net to catch those missed vaccination opportunities so that they do not fall through the cracks.
By: Jackie A. Harris, PharmD, BCPS; Executive Director, MSHP Research & Education Foundation
Dr. Joseph Walter, a PGY2 Ambulatory Care resident at CoxHealth this past residency year, was awarded the Best Resident Project during the Virtual KCHP/MSHP Spring Meeting for his project entitled “Impact of Pharmacist-led Education on Providers’ Prescribing Rates and Perceptions of Naloxone in High-Risk Opioid Patients”. With the number of naloxone prescriptions increasing by 106% from 2017 to 2018, one would expect to see that same correlation in our high-risk patient populations. Unfortunately, that is not the case with only one naloxone prescription for every 69 high-dose opioid prescription.
This prospective, observational study was conducted to evaluate the impact of pharmacist-led education had on providers’ naloxone prescription rates. In addition, the study also assessed providers’ perceptions of naloxone in high-risk patients after pharmacist-led education. Provider perceptions of naloxone in high-risk patients was assessed before and after education utilizing a Likert scale. Providers across three primary care clinics were sent an online link to pharmacist-led education on how to identify high-risk opioid patients and how to order naloxone for those patients. The
percentage of naloxone prescriptions for high-risk opioid patients were evaluated six months before education and six months after education to evaluate the effectiveness of the pharmacist-led education.
High-risk patients were defined as being 18 years or older with chronic pain receiving > 50 morphine milligram equivalent (MME). Additionally those patients 65 years or older receiving < 50 MME/day with either kidney, liver, and/or respiratory disease, concurrent use of benzodiazepines, and a history of substance use disorder were also considered high-risk.
The naloxone prescription rate in these three primary care clinics was 8% before pharmacist education and then 6% post education. Note this data was derived from 3 months. Provider perceptions of naloxone in high-risk opioid patients was assessed by the following survey questions:
Based upon the survey results, pharmacist-led education did improve their ability to identify patients at a high-risk for overdose on opioids for chronic pain, increased the likelihood of physicians prescribing naloxone alongside opioids in patients with chronic pain that are high-risk, and increased the ability of the providers to provide education on naloxone.
This study highlighted the need for pharmacist education on naloxone prescribing for high-risk opioid patients and showed the impact of that education. The pharmacists will continue to work alongside those physicians at the primary care clinics and make recommendations to prescribe naloxone in those high-risk opioid patients.
If you have any questions about Dr. Walter’s project, please contact him at firstname.lastname@example.org.