Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).

Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).

Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).

Ms. K, age 35, soon will deliver her sec­ond child. She has a 12-year history of bipolar disorder, which was well controlled with lithium, 1,200 mg/d. During her first pregnancy 3 years ago, Ms. K stopped tak­ing lithium because she was concerned about the risk of Ebstein’s anomaly. She experienced a bipolar relapse after her healthy baby was born, and developed postpartum psychosis that was treated by restarting lithium, 1,200 mg/d, and adding olanzapine, 10 mg/d.

Ms. K has continued these medications throughout her current pregnancy. She wants to breast-feed her infant and is concerned about the effects that psychotropics might have on her newborn.

Breast-feeding and medications

 

The benefits of breast-feeding for mother and infant are well-known. Despite this, some women with bipolar disorder are advised not to breast-feed or, worse, to discontinue their medications in order to breast-feed. Decisions about breast-feeding while taking medications should be based on evidence of benefits and risks to the infant, along with a discussion of the risks of untreated illness, which is high postpartum. The prescribing information for many of the medications used to treat bipolar disorder advise against breast-feeding, although there is little evidence of harm.

Drug dosages and levels in breast milk can be reported a few different ways:
   • percentage of maternal dosage mea­sured in the breast milk
   • percentage weight-adjusted maternal dosage
   • percentage of maternal plasma level, and milk-to-plasma ratio (M:P).

Daily infant dosage can be calculated by multiplying the average concentration of the drug in breast milk (mg/mL) by the average volume of milk the baby ingests in 24 hours (usually 150 mL).¹ The rela­tive infant dosage can be calculated as the percentage maternal dosage, which is the daily infant dosage (mg/kg/d) ÷ maternal dosage (mg/kg/d) × 100.¹

According to the American Academy of Pediatrics, ≤10% of the maternal dos­age is compatible with breast-feeding.¹ Most psychotropics studied fall below this threshold. Keep in mind that all published research is for breast-feeding a full-term infant; exercise caution with premature or low birth weight infants. Infants born to mothers taking a psychotropic should be monitored for withdrawal symptoms, which might be associated with antide­pressants and benzodiazepines, but other­wise are rare.

Lithium
Breast-feeding during lithium treatment has been considered contraindicated based on early reports that lithium was highly excreted in breast milk.² A 2003 study² of 11 women found that lithium was excreted in breast milk in amounts between zero and 30% of maternal dosage (mean, 12.2% ± 8.5%; median, 11.2%; 95% CI, 6.3% to 18.0%). Researchers measured serum con­centrations in 2 infants and found that 1 received 17% to 20% of the maternal dos­age, and the other showed 50%. None of the infants experienced adverse events. In a study of 10 mother-infant pairs, breast milk lithium concentration averaged 0.35 mEq/L (standard deviation [SD] = 0.10, range 0.19 to 0.48 mEq/L), with paired infant serum concentrations of 0.16 mEq/L (SD = 0.06, range 0.09 to 0.25 mEq/L).³ Some transient abnormali­ties were found in infant serum concen­trations of thyroid-stimulating hormone (TSH), blood urea nitrogen, and creatinine; there were no adverse effects on develop­ment. The authors recommend monitoring for TSH abnormalities in infants.

Olanzapine
Olanzapine prescribing information cites a study reporting that 1.8% of the maternal dosage is transferred to breast milk.⁴ Yet the olanzapine prescribing information states, “It is recommended that women receiv­ing olanzapine should not breast-feed.” Olanzapine use during breast-feeding has been studied more than many medications, in part because of a database maintained by the manufacturer. In a study using the man­ufacturer’s database (N = 102) adverse reac­tions were reported in 15.6% of the infants, with the most common being somnolence (3.9%), irritability (2%), tremor (2%), and insomnia (2%).⁵

Other second-generation antipsychotics
Aripiprazole. The only case report of aripip­razole excretion in human breast milk found a concentration of approximately 20% of the maternal plasma level and an M:P ratio of 0.18:0.2.⁶

Asenapine. According to asenapine pre­scribing information⁷ and a literature search, it is not known whether asenapine is excreted in breast milk of humans, although it is found in the milk of lactating rats.

Lurasidone. According to the lurasidone prescribing information⁸ and a literature search, it is not known whether lurasidone is excreted in human breast milk, although it is found in the milk of lactating rats.

Quetiapine. An initial study reported that 0.09% to 0.43% of the maternal dosage of quetiapine was excreted in breast milk.⁹ Further studies found excretion to be 0.09% of maternal dosage, with infant plasma levels reaching 6% of the maternal dos­age.¹⁰ A case series found that one-third of babies exposed to quetiapine during breast-feeding showed some neurodevelopmental delay, although these mothers also were taking other psychotropics.¹¹

 

Risperidone. A 2000 study¹² of risperidone in lactation reported that 0.84% weight-adjusted maternal risperidone dosage and 3.46% of its metabolite 9-hydroxyrisperi­done is transferred to the infant. A later study showed 2.3% to 4.7% of the mater­nal dosage is transferred, with no adverse events reported in infants.¹³ A case study reported no adverse events and normal neu­rodevelopment in a the child of a mother taking risperidone.¹⁴

Ziprasidone. According to the ziprasidone prescribing information¹⁵ and a literature search, is not known whether ziprasidone is excreted in human breast milk.

See the Table^{4,6-10,12,13,15} for a summary of the evidence levels of second-generation antipsychotics that are excreted in breast milk.

Other mood stabilizers
Carbamazepine has been measured in breast milk at 3.8% to 5.9% of the maternal dosage.¹⁶

Lamotrigine. In a study of 30 lactat­ing women, the breast milk contained an average of 9.2% of the maternal dosage of lamotrigine.¹⁷ Mild thrombocytosis was detected in 7 of 8 infants; no other adverse effects were reported. A case study describes a woman who breast-fed while taking lamotrigine, 850 mg/d, and who experi­enced dizziness and visual disturbances. The infant had apnea episodes followed by a cyanotic crisis, which required resuscita­tion. The infant’s plasma lamotrigine level was 4.87 μg/mL. Symptoms disappeared when the mother stopped breast-feeding.¹⁸ Lamotrigine is considered to be moderately safe in breast-feeding patients with proper monitoring. The drug also has a known safety profile because of its use in children with epilepsy.

Valproic acid. Because of its high plasma protein binding, valproic acid does not pass readily into the breast milk. Newborns receive approximately 1.4% to 1.7% of the maternal dosage.¹⁶ Caution is advised, however, because of some reported adverse events. One case reported thrombocytopenic purpura and anemia in an infant.¹⁹ Valproic acid is considered to be compatible with breast-feeding with proper monitoring.

Benzodiazepines
Benzodiazepines can be helpful adjunctive medications to aid sleep, which is essen­tial for the mother’s and infant’s health. In a prospectively recruited, retrospec­tively assessed cohort study that evaluated 124 women taking benzodiazepines while breast-feeding, adverse effects, specifically sedation, were noted in 1.6% of infants.²⁰

Future developments in prescribing information
Under a 2008 FDA recommendation, the “Nursing Mothers” section of prescribing information would be replaced with a sec­tion entitled “Lactation.” This new head­ing would include the sub-headings Risk Summary, Clinical Considerations, and Data.¹ It is expected that this new format will be more practical and will help clini­cians and patients make informed deci­sions. The prescribing changes will be in effect on June 30, 2015.²¹

 

Related Resources
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
• LactMed. http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm.
• MOTHERISK. www.motherisk.org/women/ breastfeeding.jsp.

Drug Brand Names
Aripiprazole • Abilify                    Olanzapine • Zyprexa
Asenapine • Saphris                    Quetiapine • Seroquel
Carbamazepine • Tegretol           Risperidone • Risperdal
Lamotrigine • Lamictal                 Valproic acid • Depakene
Lithium • Eskalith, Lithobid           Ziprasidone • Geodon
Lurasidone • Latuda

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. K, age 35, soon will deliver her sec­ond child. She has a 12-year history of bipolar disorder, which was well controlled with lithium, 1,200 mg/d. During her first pregnancy 3 years ago, Ms. K stopped tak­ing lithium because she was concerned about the risk of Ebstein’s anomaly. She experienced a bipolar relapse after her healthy baby was born, and developed postpartum psychosis that was treated by restarting lithium, 1,200 mg/d, and adding olanzapine, 10 mg/d.

Ms. K has continued these medications throughout her current pregnancy. She wants to breast-feed her infant and is concerned about the effects that psychotropics might have on her newborn.

Breast-feeding and medications

 

The benefits of breast-feeding for mother and infant are well-known. Despite this, some women with bipolar disorder are advised not to breast-feed or, worse, to discontinue their medications in order to breast-feed. Decisions about breast-feeding while taking medications should be based on evidence of benefits and risks to the infant, along with a discussion of the risks of untreated illness, which is high postpartum. The prescribing information for many of the medications used to treat bipolar disorder advise against breast-feeding, although there is little evidence of harm.

Drug dosages and levels in breast milk can be reported a few different ways:
   • percentage of maternal dosage mea­sured in the breast milk
   • percentage weight-adjusted maternal dosage
   • percentage of maternal plasma level, and milk-to-plasma ratio (M:P).

Daily infant dosage can be calculated by multiplying the average concentration of the drug in breast milk (mg/mL) by the average volume of milk the baby ingests in 24 hours (usually 150 mL).¹ The rela­tive infant dosage can be calculated as the percentage maternal dosage, which is the daily infant dosage (mg/kg/d) ÷ maternal dosage (mg/kg/d) × 100.¹

According to the American Academy of Pediatrics, ≤10% of the maternal dos­age is compatible with breast-feeding.¹ Most psychotropics studied fall below this threshold. Keep in mind that all published research is for breast-feeding a full-term infant; exercise caution with premature or low birth weight infants. Infants born to mothers taking a psychotropic should be monitored for withdrawal symptoms, which might be associated with antide­pressants and benzodiazepines, but other­wise are rare.

Lithium
Breast-feeding during lithium treatment has been considered contraindicated based on early reports that lithium was highly excreted in breast milk.² A 2003 study² of 11 women found that lithium was excreted in breast milk in amounts between zero and 30% of maternal dosage (mean, 12.2% ± 8.5%; median, 11.2%; 95% CI, 6.3% to 18.0%). Researchers measured serum con­centrations in 2 infants and found that 1 received 17% to 20% of the maternal dos­age, and the other showed 50%. None of the infants experienced adverse events. In a study of 10 mother-infant pairs, breast milk lithium concentration averaged 0.35 mEq/L (standard deviation [SD] = 0.10, range 0.19 to 0.48 mEq/L), with paired infant serum concentrations of 0.16 mEq/L (SD = 0.06, range 0.09 to 0.25 mEq/L).³ Some transient abnormali­ties were found in infant serum concen­trations of thyroid-stimulating hormone (TSH), blood urea nitrogen, and creatinine; there were no adverse effects on develop­ment. The authors recommend monitoring for TSH abnormalities in infants.

Olanzapine
Olanzapine prescribing information cites a study reporting that 1.8% of the maternal dosage is transferred to breast milk.⁴ Yet the olanzapine prescribing information states, “It is recommended that women receiv­ing olanzapine should not breast-feed.” Olanzapine use during breast-feeding has been studied more than many medications, in part because of a database maintained by the manufacturer. In a study using the man­ufacturer’s database (N = 102) adverse reac­tions were reported in 15.6% of the infants, with the most common being somnolence (3.9%), irritability (2%), tremor (2%), and insomnia (2%).⁵

Other second-generation antipsychotics
Aripiprazole. The only case report of aripip­razole excretion in human breast milk found a concentration of approximately 20% of the maternal plasma level and an M:P ratio of 0.18:0.2.⁶

Asenapine. According to asenapine pre­scribing information⁷ and a literature search, it is not known whether asenapine is excreted in breast milk of humans, although it is found in the milk of lactating rats.

Lurasidone. According to the lurasidone prescribing information⁸ and a literature search, it is not known whether lurasidone is excreted in human breast milk, although it is found in the milk of lactating rats.

Quetiapine. An initial study reported that 0.09% to 0.43% of the maternal dosage of quetiapine was excreted in breast milk.⁹ Further studies found excretion to be 0.09% of maternal dosage, with infant plasma levels reaching 6% of the maternal dos­age.¹⁰ A case series found that one-third of babies exposed to quetiapine during breast-feeding showed some neurodevelopmental delay, although these mothers also were taking other psychotropics.¹¹

 

Risperidone. A 2000 study¹² of risperidone in lactation reported that 0.84% weight-adjusted maternal risperidone dosage and 3.46% of its metabolite 9-hydroxyrisperi­done is transferred to the infant. A later study showed 2.3% to 4.7% of the mater­nal dosage is transferred, with no adverse events reported in infants.¹³ A case study reported no adverse events and normal neu­rodevelopment in a the child of a mother taking risperidone.¹⁴

Ziprasidone. According to the ziprasidone prescribing information¹⁵ and a literature search, is not known whether ziprasidone is excreted in human breast milk.

See the Table^{4,6-10,12,13,15} for a summary of the evidence levels of second-generation antipsychotics that are excreted in breast milk.

Other mood stabilizers
Carbamazepine has been measured in breast milk at 3.8% to 5.9% of the maternal dosage.¹⁶

Lamotrigine. In a study of 30 lactat­ing women, the breast milk contained an average of 9.2% of the maternal dosage of lamotrigine.¹⁷ Mild thrombocytosis was detected in 7 of 8 infants; no other adverse effects were reported. A case study describes a woman who breast-fed while taking lamotrigine, 850 mg/d, and who experi­enced dizziness and visual disturbances. The infant had apnea episodes followed by a cyanotic crisis, which required resuscita­tion. The infant’s plasma lamotrigine level was 4.87 μg/mL. Symptoms disappeared when the mother stopped breast-feeding.¹⁸ Lamotrigine is considered to be moderately safe in breast-feeding patients with proper monitoring. The drug also has a known safety profile because of its use in children with epilepsy.

Valproic acid. Because of its high plasma protein binding, valproic acid does not pass readily into the breast milk. Newborns receive approximately 1.4% to 1.7% of the maternal dosage.¹⁶ Caution is advised, however, because of some reported adverse events. One case reported thrombocytopenic purpura and anemia in an infant.¹⁹ Valproic acid is considered to be compatible with breast-feeding with proper monitoring.

Benzodiazepines
Benzodiazepines can be helpful adjunctive medications to aid sleep, which is essen­tial for the mother’s and infant’s health. In a prospectively recruited, retrospec­tively assessed cohort study that evaluated 124 women taking benzodiazepines while breast-feeding, adverse effects, specifically sedation, were noted in 1.6% of infants.²⁰

Future developments in prescribing information
Under a 2008 FDA recommendation, the “Nursing Mothers” section of prescribing information would be replaced with a sec­tion entitled “Lactation.” This new head­ing would include the sub-headings Risk Summary, Clinical Considerations, and Data.¹ It is expected that this new format will be more practical and will help clini­cians and patients make informed deci­sions. The prescribing changes will be in effect on June 30, 2015.²¹

 

Related Resources
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
• LactMed. http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm.
• MOTHERISK. www.motherisk.org/women/ breastfeeding.jsp.

Drug Brand Names
Aripiprazole • Abilify                    Olanzapine • Zyprexa
Asenapine • Saphris                    Quetiapine • Seroquel
Carbamazepine • Tegretol           Risperidone • Risperdal
Lamotrigine • Lamictal                 Valproic acid • Depakene
Lithium • Eskalith, Lithobid           Ziprasidone • Geodon
Lurasidone • Latuda

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. K, age 35, soon will deliver her sec­ond child. She has a 12-year history of bipolar disorder, which was well controlled with lithium, 1,200 mg/d. During her first pregnancy 3 years ago, Ms. K stopped tak­ing lithium because she was concerned about the risk of Ebstein’s anomaly. She experienced a bipolar relapse after her healthy baby was born, and developed postpartum psychosis that was treated by restarting lithium, 1,200 mg/d, and adding olanzapine, 10 mg/d.

Ms. K has continued these medications throughout her current pregnancy. She wants to breast-feed her infant and is concerned about the effects that psychotropics might have on her newborn.

Breast-feeding and medications

 

The benefits of breast-feeding for mother and infant are well-known. Despite this, some women with bipolar disorder are advised not to breast-feed or, worse, to discontinue their medications in order to breast-feed. Decisions about breast-feeding while taking medications should be based on evidence of benefits and risks to the infant, along with a discussion of the risks of untreated illness, which is high postpartum. The prescribing information for many of the medications used to treat bipolar disorder advise against breast-feeding, although there is little evidence of harm.

Drug dosages and levels in breast milk can be reported a few different ways:
   • percentage of maternal dosage mea­sured in the breast milk
   • percentage weight-adjusted maternal dosage
   • percentage of maternal plasma level, and milk-to-plasma ratio (M:P).

Daily infant dosage can be calculated by multiplying the average concentration of the drug in breast milk (mg/mL) by the average volume of milk the baby ingests in 24 hours (usually 150 mL).¹ The rela­tive infant dosage can be calculated as the percentage maternal dosage, which is the daily infant dosage (mg/kg/d) ÷ maternal dosage (mg/kg/d) × 100.¹

According to the American Academy of Pediatrics, ≤10% of the maternal dos­age is compatible with breast-feeding.¹ Most psychotropics studied fall below this threshold. Keep in mind that all published research is for breast-feeding a full-term infant; exercise caution with premature or low birth weight infants. Infants born to mothers taking a psychotropic should be monitored for withdrawal symptoms, which might be associated with antide­pressants and benzodiazepines, but other­wise are rare.

Lithium
Breast-feeding during lithium treatment has been considered contraindicated based on early reports that lithium was highly excreted in breast milk.² A 2003 study² of 11 women found that lithium was excreted in breast milk in amounts between zero and 30% of maternal dosage (mean, 12.2% ± 8.5%; median, 11.2%; 95% CI, 6.3% to 18.0%). Researchers measured serum con­centrations in 2 infants and found that 1 received 17% to 20% of the maternal dos­age, and the other showed 50%. None of the infants experienced adverse events. In a study of 10 mother-infant pairs, breast milk lithium concentration averaged 0.35 mEq/L (standard deviation [SD] = 0.10, range 0.19 to 0.48 mEq/L), with paired infant serum concentrations of 0.16 mEq/L (SD = 0.06, range 0.09 to 0.25 mEq/L).³ Some transient abnormali­ties were found in infant serum concen­trations of thyroid-stimulating hormone (TSH), blood urea nitrogen, and creatinine; there were no adverse effects on develop­ment. The authors recommend monitoring for TSH abnormalities in infants.

Olanzapine
Olanzapine prescribing information cites a study reporting that 1.8% of the maternal dosage is transferred to breast milk.⁴ Yet the olanzapine prescribing information states, “It is recommended that women receiv­ing olanzapine should not breast-feed.” Olanzapine use during breast-feeding has been studied more than many medications, in part because of a database maintained by the manufacturer. In a study using the man­ufacturer’s database (N = 102) adverse reac­tions were reported in 15.6% of the infants, with the most common being somnolence (3.9%), irritability (2%), tremor (2%), and insomnia (2%).⁵

Other second-generation antipsychotics
Aripiprazole. The only case report of aripip­razole excretion in human breast milk found a concentration of approximately 20% of the maternal plasma level and an M:P ratio of 0.18:0.2.⁶

Asenapine. According to asenapine pre­scribing information⁷ and a literature search, it is not known whether asenapine is excreted in breast milk of humans, although it is found in the milk of lactating rats.

Lurasidone. According to the lurasidone prescribing information⁸ and a literature search, it is not known whether lurasidone is excreted in human breast milk, although it is found in the milk of lactating rats.

Quetiapine. An initial study reported that 0.09% to 0.43% of the maternal dosage of quetiapine was excreted in breast milk.⁹ Further studies found excretion to be 0.09% of maternal dosage, with infant plasma levels reaching 6% of the maternal dos­age.¹⁰ A case series found that one-third of babies exposed to quetiapine during breast-feeding showed some neurodevelopmental delay, although these mothers also were taking other psychotropics.¹¹

 

Risperidone. A 2000 study¹² of risperidone in lactation reported that 0.84% weight-adjusted maternal risperidone dosage and 3.46% of its metabolite 9-hydroxyrisperi­done is transferred to the infant. A later study showed 2.3% to 4.7% of the mater­nal dosage is transferred, with no adverse events reported in infants.¹³ A case study reported no adverse events and normal neu­rodevelopment in a the child of a mother taking risperidone.¹⁴

Ziprasidone. According to the ziprasidone prescribing information¹⁵ and a literature search, is not known whether ziprasidone is excreted in human breast milk.

See the Table^{4,6-10,12,13,15} for a summary of the evidence levels of second-generation antipsychotics that are excreted in breast milk.

Other mood stabilizers
Carbamazepine has been measured in breast milk at 3.8% to 5.9% of the maternal dosage.¹⁶

Lamotrigine. In a study of 30 lactat­ing women, the breast milk contained an average of 9.2% of the maternal dosage of lamotrigine.¹⁷ Mild thrombocytosis was detected in 7 of 8 infants; no other adverse effects were reported. A case study describes a woman who breast-fed while taking lamotrigine, 850 mg/d, and who experi­enced dizziness and visual disturbances. The infant had apnea episodes followed by a cyanotic crisis, which required resuscita­tion. The infant’s plasma lamotrigine level was 4.87 μg/mL. Symptoms disappeared when the mother stopped breast-feeding.¹⁸ Lamotrigine is considered to be moderately safe in breast-feeding patients with proper monitoring. The drug also has a known safety profile because of its use in children with epilepsy.

Valproic acid. Because of its high plasma protein binding, valproic acid does not pass readily into the breast milk. Newborns receive approximately 1.4% to 1.7% of the maternal dosage.¹⁶ Caution is advised, however, because of some reported adverse events. One case reported thrombocytopenic purpura and anemia in an infant.¹⁹ Valproic acid is considered to be compatible with breast-feeding with proper monitoring.

Benzodiazepines
Benzodiazepines can be helpful adjunctive medications to aid sleep, which is essen­tial for the mother’s and infant’s health. In a prospectively recruited, retrospec­tively assessed cohort study that evaluated 124 women taking benzodiazepines while breast-feeding, adverse effects, specifically sedation, were noted in 1.6% of infants.²⁰

Future developments in prescribing information
Under a 2008 FDA recommendation, the “Nursing Mothers” section of prescribing information would be replaced with a sec­tion entitled “Lactation.” This new head­ing would include the sub-headings Risk Summary, Clinical Considerations, and Data.¹ It is expected that this new format will be more practical and will help clini­cians and patients make informed deci­sions. The prescribing changes will be in effect on June 30, 2015.²¹

 

Related Resources
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
• LactMed. http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm.
• MOTHERISK. www.motherisk.org/women/ breastfeeding.jsp.

Drug Brand Names
Aripiprazole • Abilify                    Olanzapine • Zyprexa
Asenapine • Saphris                    Quetiapine • Seroquel
Carbamazepine • Tegretol           Risperidone • Risperdal
Lamotrigine • Lamictal                 Valproic acid • Depakene
Lithium • Eskalith, Lithobid           Ziprasidone • Geodon
Lurasidone • Latuda

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Physicians hardly need the Health Insurance Portability and Accountability Act (HIPAA) to remind them how important it is to safe­guard their patients’ records. Physicians understand that patient information is sen­sitive and it would be disastrous if their files became public or fell into the wrong hands. However, the use of health infor­mation technology to record patient infor­mation, although beneficial for medical professionals and patients, poses risks to patient privacy.¹

HIPAA requires clinicians and health care systems to protect patient information, whether it is maintained in an electronic health records system, stored on a mobile device, or transmitted via e-mail to another physician. The U.S. Department of Health and Human Services will increase HIPAA audits this year to make sure that medical practices have taken measures to protect their patients’ health information. Physicians and other clinicians can take advantage of cloud-based file-sharing services, such as Dropbox, without running afoul of HIPAA.

Mobile computing, the cloud, and patient information: A risky combination
Although mobile computing and cloud-based file-sharing sites such as Dropbox and Google Drive allow physicians to take notes on a tablet, annotate those notes on a laptop, and share them with a physician who views them on his (her) desktop, this free flow of information makes it more dif­ficult to stay compliant with HIPAA.

Dropbox and other file-sharing services encrypt documents while they’re stored in the cloud but the files are unprotected when downloaded to a device. E-mail, which isn’t as versatile or useful as these services, also is not HIPAA-compliant unless the files are encrypted.

Often, small psychiatric practices use these online services and e-mail even if they’re aware of the risks because they don’t have time to research a better solu­tion. Or they might resort to faxing or even snail-mailing documents, losing out on the increased productivity that the cloud can provide.

Secure technologies satisfy auditors
A number of tools exist to help physicians seamlessly integrate the encryption nec­essary to keep their patients’ records safe and meet HIPAA security requirements. Here’s a look at 3 options.

Sookasa (plus Dropbox). One option is to invest in a software product designed to encrypt documents shared through cloud-based services. This type of soft­ware creates a compliance “shield” around files stored on the cloud, converting files into HIPAA safe havens. The files are encrypted when synced to new devices or shared with other users, meaning they’re protected no matter where they reside.²

Sookasa is an online service that encrypts files shared and stored in Dropbox. The company plans to extend its support to other popular cloud services such as Google Drive and Microsoft OneDrive. Sookasa also audits and controls access to encrypted files, so that patient data can be blocked even if a device is lost or sto­ len. Sookasa users also can share files via e-mail with added encryption and authen­tication to make sure only the authorized receiver gets the documents.²

TigerText. Regular SMS text messages on your mobile phone aren’t compliant with HIPAA, but TigerText replicates the tex­ting experience in a secure way. Instead of being stored on your mobile phone, mes­sages sent through TigerText are stored on the company’s servers. Messages sent through the application can’t be saved, copied, or forwarded to other recipients. TigerText messages also are deleted, either after a set time period or after they’ve been read. Because the messages aren’t stored on phones, a lost or stolen phone won’t result in a data breach and a HIPAA violation.3

Secure text messaging won’t help physi­cians store and manage large amounts of patient files, but it’s a must-have if they use texting to communicate about patient care.

DataMotion SecureMail provides e-mail encryption services to health care orga­nizations and other enterprises. Using a decryption key, authorized users can open and read the encrypted e-mails, which are HIPAA-compliant.⁴ This method is supe­rior to other services that encrypt e-mails on the server. Several providers, such as Google’s e-mail encryption service Postini, ensure that e-mails are encrypted when they are stored on the server; however, the body text and attachments included in specific e-mails are not encrypted on the senders’ and receivers’ devices. If you lose a connected device, you would still be at risk of a HIPAA breach.

DataMotion’s SecureMail provides detailed tracking and logging of e-mails, which is necessary for auditing purposes. The product also works on mobile devices.

E-mail is a helpful tool for quickly shar­ing files and an e-mail encryption product such as SecureMail makes it possible to do so securely. Other e-mail encryption prod­ucts do not securely store and back up all files in a centralized way.

 

DisclosureDr. Cidon is CEO and Co-founder of Sookasa.

Physicians hardly need the Health Insurance Portability and Accountability Act (HIPAA) to remind them how important it is to safe­guard their patients’ records. Physicians understand that patient information is sen­sitive and it would be disastrous if their files became public or fell into the wrong hands. However, the use of health infor­mation technology to record patient infor­mation, although beneficial for medical professionals and patients, poses risks to patient privacy.¹

HIPAA requires clinicians and health care systems to protect patient information, whether it is maintained in an electronic health records system, stored on a mobile device, or transmitted via e-mail to another physician. The U.S. Department of Health and Human Services will increase HIPAA audits this year to make sure that medical practices have taken measures to protect their patients’ health information. Physicians and other clinicians can take advantage of cloud-based file-sharing services, such as Dropbox, without running afoul of HIPAA.

Mobile computing, the cloud, and patient information: A risky combination
Although mobile computing and cloud-based file-sharing sites such as Dropbox and Google Drive allow physicians to take notes on a tablet, annotate those notes on a laptop, and share them with a physician who views them on his (her) desktop, this free flow of information makes it more dif­ficult to stay compliant with HIPAA.

Dropbox and other file-sharing services encrypt documents while they’re stored in the cloud but the files are unprotected when downloaded to a device. E-mail, which isn’t as versatile or useful as these services, also is not HIPAA-compliant unless the files are encrypted.

Often, small psychiatric practices use these online services and e-mail even if they’re aware of the risks because they don’t have time to research a better solu­tion. Or they might resort to faxing or even snail-mailing documents, losing out on the increased productivity that the cloud can provide.

Secure technologies satisfy auditors
A number of tools exist to help physicians seamlessly integrate the encryption nec­essary to keep their patients’ records safe and meet HIPAA security requirements. Here’s a look at 3 options.

Sookasa (plus Dropbox). One option is to invest in a software product designed to encrypt documents shared through cloud-based services. This type of soft­ware creates a compliance “shield” around files stored on the cloud, converting files into HIPAA safe havens. The files are encrypted when synced to new devices or shared with other users, meaning they’re protected no matter where they reside.²

Sookasa is an online service that encrypts files shared and stored in Dropbox. The company plans to extend its support to other popular cloud services such as Google Drive and Microsoft OneDrive. Sookasa also audits and controls access to encrypted files, so that patient data can be blocked even if a device is lost or sto­ len. Sookasa users also can share files via e-mail with added encryption and authen­tication to make sure only the authorized receiver gets the documents.²

TigerText. Regular SMS text messages on your mobile phone aren’t compliant with HIPAA, but TigerText replicates the tex­ting experience in a secure way. Instead of being stored on your mobile phone, mes­sages sent through TigerText are stored on the company’s servers. Messages sent through the application can’t be saved, copied, or forwarded to other recipients. TigerText messages also are deleted, either after a set time period or after they’ve been read. Because the messages aren’t stored on phones, a lost or stolen phone won’t result in a data breach and a HIPAA violation.3

Secure text messaging won’t help physi­cians store and manage large amounts of patient files, but it’s a must-have if they use texting to communicate about patient care.

DataMotion SecureMail provides e-mail encryption services to health care orga­nizations and other enterprises. Using a decryption key, authorized users can open and read the encrypted e-mails, which are HIPAA-compliant.⁴ This method is supe­rior to other services that encrypt e-mails on the server. Several providers, such as Google’s e-mail encryption service Postini, ensure that e-mails are encrypted when they are stored on the server; however, the body text and attachments included in specific e-mails are not encrypted on the senders’ and receivers’ devices. If you lose a connected device, you would still be at risk of a HIPAA breach.

DataMotion’s SecureMail provides detailed tracking and logging of e-mails, which is necessary for auditing purposes. The product also works on mobile devices.

E-mail is a helpful tool for quickly shar­ing files and an e-mail encryption product such as SecureMail makes it possible to do so securely. Other e-mail encryption prod­ucts do not securely store and back up all files in a centralized way.

 

DisclosureDr. Cidon is CEO and Co-founder of Sookasa.

Physicians hardly need the Health Insurance Portability and Accountability Act (HIPAA) to remind them how important it is to safe­guard their patients’ records. Physicians understand that patient information is sen­sitive and it would be disastrous if their files became public or fell into the wrong hands. However, the use of health infor­mation technology to record patient infor­mation, although beneficial for medical professionals and patients, poses risks to patient privacy.¹

HIPAA requires clinicians and health care systems to protect patient information, whether it is maintained in an electronic health records system, stored on a mobile device, or transmitted via e-mail to another physician. The U.S. Department of Health and Human Services will increase HIPAA audits this year to make sure that medical practices have taken measures to protect their patients’ health information. Physicians and other clinicians can take advantage of cloud-based file-sharing services, such as Dropbox, without running afoul of HIPAA.

Mobile computing, the cloud, and patient information: A risky combination
Although mobile computing and cloud-based file-sharing sites such as Dropbox and Google Drive allow physicians to take notes on a tablet, annotate those notes on a laptop, and share them with a physician who views them on his (her) desktop, this free flow of information makes it more dif­ficult to stay compliant with HIPAA.

Dropbox and other file-sharing services encrypt documents while they’re stored in the cloud but the files are unprotected when downloaded to a device. E-mail, which isn’t as versatile or useful as these services, also is not HIPAA-compliant unless the files are encrypted.

Often, small psychiatric practices use these online services and e-mail even if they’re aware of the risks because they don’t have time to research a better solu­tion. Or they might resort to faxing or even snail-mailing documents, losing out on the increased productivity that the cloud can provide.

Secure technologies satisfy auditors
A number of tools exist to help physicians seamlessly integrate the encryption nec­essary to keep their patients’ records safe and meet HIPAA security requirements. Here’s a look at 3 options.

Sookasa (plus Dropbox). One option is to invest in a software product designed to encrypt documents shared through cloud-based services. This type of soft­ware creates a compliance “shield” around files stored on the cloud, converting files into HIPAA safe havens. The files are encrypted when synced to new devices or shared with other users, meaning they’re protected no matter where they reside.²

Sookasa is an online service that encrypts files shared and stored in Dropbox. The company plans to extend its support to other popular cloud services such as Google Drive and Microsoft OneDrive. Sookasa also audits and controls access to encrypted files, so that patient data can be blocked even if a device is lost or sto­ len. Sookasa users also can share files via e-mail with added encryption and authen­tication to make sure only the authorized receiver gets the documents.²

TigerText. Regular SMS text messages on your mobile phone aren’t compliant with HIPAA, but TigerText replicates the tex­ting experience in a secure way. Instead of being stored on your mobile phone, mes­sages sent through TigerText are stored on the company’s servers. Messages sent through the application can’t be saved, copied, or forwarded to other recipients. TigerText messages also are deleted, either after a set time period or after they’ve been read. Because the messages aren’t stored on phones, a lost or stolen phone won’t result in a data breach and a HIPAA violation.3

Secure text messaging won’t help physi­cians store and manage large amounts of patient files, but it’s a must-have if they use texting to communicate about patient care.

DataMotion SecureMail provides e-mail encryption services to health care orga­nizations and other enterprises. Using a decryption key, authorized users can open and read the encrypted e-mails, which are HIPAA-compliant.⁴ This method is supe­rior to other services that encrypt e-mails on the server. Several providers, such as Google’s e-mail encryption service Postini, ensure that e-mails are encrypted when they are stored on the server; however, the body text and attachments included in specific e-mails are not encrypted on the senders’ and receivers’ devices. If you lose a connected device, you would still be at risk of a HIPAA breach.

DataMotion’s SecureMail provides detailed tracking and logging of e-mails, which is necessary for auditing purposes. The product also works on mobile devices.

E-mail is a helpful tool for quickly shar­ing files and an e-mail encryption product such as SecureMail makes it possible to do so securely. Other e-mail encryption prod­ucts do not securely store and back up all files in a centralized way.

 

DisclosureDr. Cidon is CEO and Co-founder of Sookasa.

3/24/15, Day 3 at SGS

Many topics, many learning opportunities   

The morning’s focus topics at SGS were divided up in small-group academic roundtables, with 15 experts in the field providing authoritative know-how and guidance to attendees. Topics ranged from tips for in-bag tissue extraction, endometriosis surgery, surviving health care transformation, cost-effectiveness, and single-site surgery to innovative treatments for fecal incontinence.

In the main hall, the fourth scientific session included oral presentations and videos that focused on anatomic landmarks and variations and included data presentation from an interesting prospective randomized trial in which the authors found bladder support is reduced by pregnancy, regardless of delivery method.

The highlight of the morning was certainly the debate over "power" morcellation. Dr. Cheryl Iglesia moderated in her charming and comical manner. Dr. Andrew Sokol and Dr. Jubilee Brown argued that power morcellation still should be available to a select group of appropriately chosen, low-risk women, and backed their arguments up with solid data. Dr. Eric Sokol, Andrew’s twin (and better looking, per him) brother, and Dr. Carl Zimmerman argued against the use of power morcellation, instead urging everyone in the audience to perform more vaginal hysterectomies. Though spirited and based largely on sound medical evidence, the debate did not have a clear winner. The overall consensus seemed to be that this controversial topic needed further evaluation and more data to support either claim.

"Sesame street graduates” and andragogy

We were then honored to have Vice President for Education, American College of Obstetricians and Gynecologists Dr. Sandra Carson as the esteemed TeLinde Lecturer. Her talk, “Teaching Medicine and Surgery to Sesame Street Graduates,” outlined the challenges in teaching surgery to a new generation of ObGyn residents as well as identified opportunities for improvement. She restated what seems to be the running theme at SGS this year: young faculty and residents are losing the skill for vaginal hysterectomy.

Dr. Carson introduced members of the audience to the adult theory of learning called andragogy. Adults like active learning, which is problem centered, rather than content oriented; linking new concepts to prior experience; and learning what is relevant to them, she noted. Then she shared ACOG’s strategies for applying these learning principles in resident education. She discussed ACOG’s recently formed Vaginal Hysterectomy Teaching Taskforce, which has put together a simulation consortium online toolkit and a surgical skills module to help educate residents on vaginal hysterectomy techniques. This toolkit and module can be accessed by doing a quick search after signing into the ACOG Web site.

Dr. Carson, a reproductive endocrinologist formerly at Brown University, is also now an honorary member of SGS.

Wise words from a wise physician

In his presidential address Dr. Stephen Metz acknowledged that all physicians are subject to even subtle “conflicts of interest,” reminding us to treat our patients as people not as a disease or a procedure.

“What does my patient really want from me? She wants me to get to know her to develop the right recommendations for her,” he said. His career has spanned multiple decades, and his service to the field of gynecology is outstanding. He received a well-deserved standing ovation at the end of his address.

Sport and socialization a necessity in sunny Florida!

The afternoon adjourned after the business meeting, and members were able to play golf, tennis, paddleboard in Winter Park, or just relax at the resort. Congratulations to the winners of the golf tournament (Drs. Hopkins, Rasmussen, Hurd, and Flora) and the tennis tournament (Dr. Ted Lee)!

Everyone convened at the outside terrace for the evening “Mojito Night in the Caribbean” reception, sharing good times, cocktails, and hors d’oeuvres. Proceeds from each ticket sold helped support Surgeons Helping Advance Research and Education (SHARE).

Tomorrow looks to be an excellent conclusion to a well-planned and very well-executed meeting. Kudos, and large thanks, to the SGS leadership.

3/23/15, Day 2 at SGS

Surgeons from 17 countries converge

The first day of the SGS scientific sessions was another energetic and interactive day. Sixteen new SGS members were recognized and welcomed in the main conference hall. Dr. Charles Rardin presented a brief overview and some basic statistics related to this year’s meeting—the largest ever in the history of SGS. A total of 401 attendees representing 17 countries are here in Orlando for SGS 2015! 

In the first scientific session, oral presentations touched on the subjects of preoperative dexamethasone use, vaginal packing, surgical site infections, and a new treatment modality for fecal incontinence. An excellent technique video on laparoscopic ureterolysis by Dr. Cara King then followed, in which she demonstrated excellent surgical skills with amazingly clear anatomy. Her video was recognized later in the day with a well-deserved award—congratulations! 

 

A short break in the exhibit hall allowed for mingling with other attendees, many of whom have been active on social media surrounding the meeting, and for visiting the booths of the industry sponsors. The second scientific session then picked up where the first left off, with more scientifically sound research presented on such topics as mechanical bowel preparation use in laparoscopy and pelvic floor disorders in women with gynecologic malignancies.

No room for fads in gyn surgery

Dr. David Grimes, a true leader in our field, provided an exceptional keynote address, “Is Teaching Evidence-Based Surgery Possible?" He shared his expertise of evidence-based medicine, and described (in sometimes very comical but always stimulating and provocative terms) the need for incorporating evidence-based surgery in gynecology. He urged us to strive to do best by our patients by applying evidenced-based practices rather than following fads and gizmos.

Gyn surgery training: Have we reached a “perfect storm”?

The afternoon brought with it a panel discussion on "Teaching the Next Generation of GYN Surgeons," with Dr. Hal Lawrence moderating and Dr. Mark Walters and Dr. Dee Fenner serving as panelists. They discussed the future of ObGyn residency training in great detail: increasing subspecialization, a stable birth rate, declining hysterectomy rates, increasing safety and quality monitoring, and increased access to data and informed consumers. All of these trends were highlighted as reasons for a perfect storm in gynecologic surgery training. In addition, the panel presented some surprising statistics: 

• The majority of hysterectomies in the United States are being done by surgeons who perform less than 1 per month.
• The higher volume surgeons provide higher value and tend to utilize more minimally invasive approaches.

Videofest!

The scientific day concluded with a videofest that included complex robotic, laparoscopic, hysteroscopic, cystoscopic, and vaginal surgeries, demonstrating the surgical talents and ingenuity of SGS members.

Simultaneously, the Fellows’ Pelvic Research Network (FPRN) met to update their ongoing projects and to review new proposals. The meeting sought to unite FPRMS and MIS fellows to conduct multicenter studies. This was an enlightening and engaging session, which should give everyone great hope to see the creativity and energy of the next generation of researchers.

A grounder for attendees

All in attendance were treated to a unique, eye-opening, motivational, and very moving talk by Professor (and Sir) Ajay Rane, MD, PhD from Australia on female genital mutilation. He stressed the importance of respecting women for who they are, not what they do.

“My idea of feminism is applauding a woman who gives birth. Celebrate women for who they are," he said. He highlighted the work being done by his team in Australia and India, and urged everyone in attendance to become more aware of the staggering statistics and reality of female genital mutilation.

The jam-packed day wrapped with the awards ceremony in the main hall. Lifelong mentors were honored by their mentees and SGS President Dr. Stephen Metz and Scientific Program Chair Dr. Charles Rardin presented various awards to those who had submitted and presented novel and groundbreaking research.

One last surprise

The President’s Reception in the exhibit hall was lively, with meeting sponsors, colleagues, and friends in attendance. And, of course, a visit from special guest! (Thanks to SGS Fellow Christina Saad, MD @XtinaSaad for the pic!)

See you all tomorrow for another educational, enlightening, and spirited day at #SGS2015! 

3/22/15. DAY 1 AT SGS

A focus on evidence-based medicine

Strong analytic skills (of your own research as well as the published literature) translates to better patient care, was the underlying theme of the opening postgraduate course here in Orlando, Florida, for day 1 of the 41st annual meeting of the Society of Gynecologic Surgeons.

Building on the success of last year’s course on evidence-based medicine (EBM), Dr. Vivian Sung and Dr. Ike Rahn put together an amazing team to review and apply the principles of so-called EBM, a workshop that was in part sponsored by ABOG.

A quick introduction to EBM principles by Dr. Thomas Wheeler was followed by small break-out groups, where attendees used the PICO-DD model to define a Population, Intervention, Comparator, Outcomes, Duration, and study Design. Further talks focused on the benefits and caveats of randomized controlled trials (RCTs), surrogate and intermediate outcomes, and systematic reviews and meta-analyses.

Dr. Ethan Balk cautioned us to consider the costly and underpowered RCT, and lack of generalizability needed to define rigorous study inclusion and outcome criteria. Dr. Sung then pointed out that, while the perfect surrogate outcome would allow us to shorten study lengths (and save money), the seduction of association and causation can lead to some questionable conclusions.

 

When using a clinical practice guideline, Dr. Miles Murphy indicated that a systematic review needs to be included, although a meta-analysis is not always required. The poor quality and paucity of RCTs for most patient populations is what limits us.

Dr. Rahn gave an excellent presentation on subgroup analysis, recommending to attendees that they perform these analyses cautiously, describe which groups are analyzed, and have statistical back-up for power and P value calculations.

Dr. Kristen Matteson then spoke about interpreting the literature on screening and diagnostic tests, giving a thorough but understandable review of the basics of statistics. Dr. John Wong rounded out the course, suggesting that because RCTs are expensive and comprise less than 5% of published studies, the analysis of observational studies as RCTs would allow us to better inform our patients and our colleagues on the best treatments, using patient-centered outcomes, efficacy data, and multiple providers. He urged us all to be more skeptical and ask critical questions when dealing with evidence in medicine.

Sharpening ultrasonography skills

Simultaneously, others attended a hands-on learning course on comprehensive pelvic floor ultrasonography, including transperineal, endovaginal, and endoanal imaging, organized by Dr. Abbas Shobeiri.

Tips for the difficult hysterectomy

Dr. Ted Lee (with help from Drs. Arnold P. Advincula, Rosanne Kho, and Matthew Seidhoff) prepared a surgical tutorial on laparoscopic, robotic, and vaginal strategies and techniques for approaching the difficult hysterectomy. The course was phenomenal, as described by many of the members fortunate enough to learn some of the tips and tricks demonstrated by the master surgeons.

Training for the NIH application process

Following the postgraduate courses, Dr. Katherine Hartmann led an “NIH Application Training Camp,” an offering supported by SGS research donations and a generous donation from Dr. Holly Richter. Dr. Hartmann provided in-depth insight into the world of NIH grant funding and provided background prep for a K or R award application. A mock NIH application study section, in which two actual applications were reviewed, demystified the process of grant review (and rejection). 

A social end to day 1

To end the first day, a welcome reception was held where residents, fellows, and attendings from different fields of ObGyn mingled and shared drinks, stories, and good laughs.

The "social" activities continue on social media for the rest of the conference. Follow #SGS2015, @gynsurgery, @obgmanagement, and @sukrantmehta for more!

3/24/15, Day 3 at SGS

Many topics, many learning opportunities   

The morning’s focus topics at SGS were divided up in small-group academic roundtables, with 15 experts in the field providing authoritative know-how and guidance to attendees. Topics ranged from tips for in-bag tissue extraction, endometriosis surgery, surviving health care transformation, cost-effectiveness, and single-site surgery to innovative treatments for fecal incontinence.

In the main hall, the fourth scientific session included oral presentations and videos that focused on anatomic landmarks and variations and included data presentation from an interesting prospective randomized trial in which the authors found bladder support is reduced by pregnancy, regardless of delivery method.

The highlight of the morning was certainly the debate over "power" morcellation. Dr. Cheryl Iglesia moderated in her charming and comical manner. Dr. Andrew Sokol and Dr. Jubilee Brown argued that power morcellation still should be available to a select group of appropriately chosen, low-risk women, and backed their arguments up with solid data. Dr. Eric Sokol, Andrew’s twin (and better looking, per him) brother, and Dr. Carl Zimmerman argued against the use of power morcellation, instead urging everyone in the audience to perform more vaginal hysterectomies. Though spirited and based largely on sound medical evidence, the debate did not have a clear winner. The overall consensus seemed to be that this controversial topic needed further evaluation and more data to support either claim.

"Sesame street graduates” and andragogy

We were then honored to have Vice President for Education, American College of Obstetricians and Gynecologists Dr. Sandra Carson as the esteemed TeLinde Lecturer. Her talk, “Teaching Medicine and Surgery to Sesame Street Graduates,” outlined the challenges in teaching surgery to a new generation of ObGyn residents as well as identified opportunities for improvement. She restated what seems to be the running theme at SGS this year: young faculty and residents are losing the skill for vaginal hysterectomy.

Dr. Carson introduced members of the audience to the adult theory of learning called andragogy. Adults like active learning, which is problem centered, rather than content oriented; linking new concepts to prior experience; and learning what is relevant to them, she noted. Then she shared ACOG’s strategies for applying these learning principles in resident education. She discussed ACOG’s recently formed Vaginal Hysterectomy Teaching Taskforce, which has put together a simulation consortium online toolkit and a surgical skills module to help educate residents on vaginal hysterectomy techniques. This toolkit and module can be accessed by doing a quick search after signing into the ACOG Web site.

Dr. Carson, a reproductive endocrinologist formerly at Brown University, is also now an honorary member of SGS.

Wise words from a wise physician

In his presidential address Dr. Stephen Metz acknowledged that all physicians are subject to even subtle “conflicts of interest,” reminding us to treat our patients as people not as a disease or a procedure.

“What does my patient really want from me? She wants me to get to know her to develop the right recommendations for her,” he said. His career has spanned multiple decades, and his service to the field of gynecology is outstanding. He received a well-deserved standing ovation at the end of his address.

Sport and socialization a necessity in sunny Florida!

The afternoon adjourned after the business meeting, and members were able to play golf, tennis, paddleboard in Winter Park, or just relax at the resort. Congratulations to the winners of the golf tournament (Drs. Hopkins, Rasmussen, Hurd, and Flora) and the tennis tournament (Dr. Ted Lee)!

Everyone convened at the outside terrace for the evening “Mojito Night in the Caribbean” reception, sharing good times, cocktails, and hors d’oeuvres. Proceeds from each ticket sold helped support Surgeons Helping Advance Research and Education (SHARE).

Tomorrow looks to be an excellent conclusion to a well-planned and very well-executed meeting. Kudos, and large thanks, to the SGS leadership.

3/23/15, Day 2 at SGS

Surgeons from 17 countries converge

The first day of the SGS scientific sessions was another energetic and interactive day. Sixteen new SGS members were recognized and welcomed in the main conference hall. Dr. Charles Rardin presented a brief overview and some basic statistics related to this year’s meeting—the largest ever in the history of SGS. A total of 401 attendees representing 17 countries are here in Orlando for SGS 2015! 

In the first scientific session, oral presentations touched on the subjects of preoperative dexamethasone use, vaginal packing, surgical site infections, and a new treatment modality for fecal incontinence. An excellent technique video on laparoscopic ureterolysis by Dr. Cara King then followed, in which she demonstrated excellent surgical skills with amazingly clear anatomy. Her video was recognized later in the day with a well-deserved award—congratulations! 

 

A short break in the exhibit hall allowed for mingling with other attendees, many of whom have been active on social media surrounding the meeting, and for visiting the booths of the industry sponsors. The second scientific session then picked up where the first left off, with more scientifically sound research presented on such topics as mechanical bowel preparation use in laparoscopy and pelvic floor disorders in women with gynecologic malignancies.

No room for fads in gyn surgery

Dr. David Grimes, a true leader in our field, provided an exceptional keynote address, “Is Teaching Evidence-Based Surgery Possible?" He shared his expertise of evidence-based medicine, and described (in sometimes very comical but always stimulating and provocative terms) the need for incorporating evidence-based surgery in gynecology. He urged us to strive to do best by our patients by applying evidenced-based practices rather than following fads and gizmos.

Gyn surgery training: Have we reached a “perfect storm”?

The afternoon brought with it a panel discussion on "Teaching the Next Generation of GYN Surgeons," with Dr. Hal Lawrence moderating and Dr. Mark Walters and Dr. Dee Fenner serving as panelists. They discussed the future of ObGyn residency training in great detail: increasing subspecialization, a stable birth rate, declining hysterectomy rates, increasing safety and quality monitoring, and increased access to data and informed consumers. All of these trends were highlighted as reasons for a perfect storm in gynecologic surgery training. In addition, the panel presented some surprising statistics: 

• The majority of hysterectomies in the United States are being done by surgeons who perform less than 1 per month.
• The higher volume surgeons provide higher value and tend to utilize more minimally invasive approaches.

Videofest!

The scientific day concluded with a videofest that included complex robotic, laparoscopic, hysteroscopic, cystoscopic, and vaginal surgeries, demonstrating the surgical talents and ingenuity of SGS members.

Simultaneously, the Fellows’ Pelvic Research Network (FPRN) met to update their ongoing projects and to review new proposals. The meeting sought to unite FPRMS and MIS fellows to conduct multicenter studies. This was an enlightening and engaging session, which should give everyone great hope to see the creativity and energy of the next generation of researchers.

A grounder for attendees

All in attendance were treated to a unique, eye-opening, motivational, and very moving talk by Professor (and Sir) Ajay Rane, MD, PhD from Australia on female genital mutilation. He stressed the importance of respecting women for who they are, not what they do.

“My idea of feminism is applauding a woman who gives birth. Celebrate women for who they are," he said. He highlighted the work being done by his team in Australia and India, and urged everyone in attendance to become more aware of the staggering statistics and reality of female genital mutilation.

The jam-packed day wrapped with the awards ceremony in the main hall. Lifelong mentors were honored by their mentees and SGS President Dr. Stephen Metz and Scientific Program Chair Dr. Charles Rardin presented various awards to those who had submitted and presented novel and groundbreaking research.

One last surprise

The President’s Reception in the exhibit hall was lively, with meeting sponsors, colleagues, and friends in attendance. And, of course, a visit from special guest! (Thanks to SGS Fellow Christina Saad, MD @XtinaSaad for the pic!)

See you all tomorrow for another educational, enlightening, and spirited day at #SGS2015! 

3/22/15. DAY 1 AT SGS

A focus on evidence-based medicine

Strong analytic skills (of your own research as well as the published literature) translates to better patient care, was the underlying theme of the opening postgraduate course here in Orlando, Florida, for day 1 of the 41st annual meeting of the Society of Gynecologic Surgeons.

Building on the success of last year’s course on evidence-based medicine (EBM), Dr. Vivian Sung and Dr. Ike Rahn put together an amazing team to review and apply the principles of so-called EBM, a workshop that was in part sponsored by ABOG.

A quick introduction to EBM principles by Dr. Thomas Wheeler was followed by small break-out groups, where attendees used the PICO-DD model to define a Population, Intervention, Comparator, Outcomes, Duration, and study Design. Further talks focused on the benefits and caveats of randomized controlled trials (RCTs), surrogate and intermediate outcomes, and systematic reviews and meta-analyses.

Dr. Ethan Balk cautioned us to consider the costly and underpowered RCT, and lack of generalizability needed to define rigorous study inclusion and outcome criteria. Dr. Sung then pointed out that, while the perfect surrogate outcome would allow us to shorten study lengths (and save money), the seduction of association and causation can lead to some questionable conclusions.

 

When using a clinical practice guideline, Dr. Miles Murphy indicated that a systematic review needs to be included, although a meta-analysis is not always required. The poor quality and paucity of RCTs for most patient populations is what limits us.

Dr. Rahn gave an excellent presentation on subgroup analysis, recommending to attendees that they perform these analyses cautiously, describe which groups are analyzed, and have statistical back-up for power and P value calculations.

Dr. Kristen Matteson then spoke about interpreting the literature on screening and diagnostic tests, giving a thorough but understandable review of the basics of statistics. Dr. John Wong rounded out the course, suggesting that because RCTs are expensive and comprise less than 5% of published studies, the analysis of observational studies as RCTs would allow us to better inform our patients and our colleagues on the best treatments, using patient-centered outcomes, efficacy data, and multiple providers. He urged us all to be more skeptical and ask critical questions when dealing with evidence in medicine.

Sharpening ultrasonography skills

Simultaneously, others attended a hands-on learning course on comprehensive pelvic floor ultrasonography, including transperineal, endovaginal, and endoanal imaging, organized by Dr. Abbas Shobeiri.

Tips for the difficult hysterectomy

Dr. Ted Lee (with help from Drs. Arnold P. Advincula, Rosanne Kho, and Matthew Seidhoff) prepared a surgical tutorial on laparoscopic, robotic, and vaginal strategies and techniques for approaching the difficult hysterectomy. The course was phenomenal, as described by many of the members fortunate enough to learn some of the tips and tricks demonstrated by the master surgeons.

Training for the NIH application process

Following the postgraduate courses, Dr. Katherine Hartmann led an “NIH Application Training Camp,” an offering supported by SGS research donations and a generous donation from Dr. Holly Richter. Dr. Hartmann provided in-depth insight into the world of NIH grant funding and provided background prep for a K or R award application. A mock NIH application study section, in which two actual applications were reviewed, demystified the process of grant review (and rejection). 

A social end to day 1

To end the first day, a welcome reception was held where residents, fellows, and attendings from different fields of ObGyn mingled and shared drinks, stories, and good laughs.

The "social" activities continue on social media for the rest of the conference. Follow #SGS2015, @gynsurgery, @obgmanagement, and @sukrantmehta for more!

3/24/15, Day 3 at SGS

Many topics, many learning opportunities   

The morning’s focus topics at SGS were divided up in small-group academic roundtables, with 15 experts in the field providing authoritative know-how and guidance to attendees. Topics ranged from tips for in-bag tissue extraction, endometriosis surgery, surviving health care transformation, cost-effectiveness, and single-site surgery to innovative treatments for fecal incontinence.

In the main hall, the fourth scientific session included oral presentations and videos that focused on anatomic landmarks and variations and included data presentation from an interesting prospective randomized trial in which the authors found bladder support is reduced by pregnancy, regardless of delivery method.

The highlight of the morning was certainly the debate over "power" morcellation. Dr. Cheryl Iglesia moderated in her charming and comical manner. Dr. Andrew Sokol and Dr. Jubilee Brown argued that power morcellation still should be available to a select group of appropriately chosen, low-risk women, and backed their arguments up with solid data. Dr. Eric Sokol, Andrew’s twin (and better looking, per him) brother, and Dr. Carl Zimmerman argued against the use of power morcellation, instead urging everyone in the audience to perform more vaginal hysterectomies. Though spirited and based largely on sound medical evidence, the debate did not have a clear winner. The overall consensus seemed to be that this controversial topic needed further evaluation and more data to support either claim.

"Sesame street graduates” and andragogy

We were then honored to have Vice President for Education, American College of Obstetricians and Gynecologists Dr. Sandra Carson as the esteemed TeLinde Lecturer. Her talk, “Teaching Medicine and Surgery to Sesame Street Graduates,” outlined the challenges in teaching surgery to a new generation of ObGyn residents as well as identified opportunities for improvement. She restated what seems to be the running theme at SGS this year: young faculty and residents are losing the skill for vaginal hysterectomy.

Dr. Carson introduced members of the audience to the adult theory of learning called andragogy. Adults like active learning, which is problem centered, rather than content oriented; linking new concepts to prior experience; and learning what is relevant to them, she noted. Then she shared ACOG’s strategies for applying these learning principles in resident education. She discussed ACOG’s recently formed Vaginal Hysterectomy Teaching Taskforce, which has put together a simulation consortium online toolkit and a surgical skills module to help educate residents on vaginal hysterectomy techniques. This toolkit and module can be accessed by doing a quick search after signing into the ACOG Web site.

Dr. Carson, a reproductive endocrinologist formerly at Brown University, is also now an honorary member of SGS.

Wise words from a wise physician

In his presidential address Dr. Stephen Metz acknowledged that all physicians are subject to even subtle “conflicts of interest,” reminding us to treat our patients as people not as a disease or a procedure.

“What does my patient really want from me? She wants me to get to know her to develop the right recommendations for her,” he said. His career has spanned multiple decades, and his service to the field of gynecology is outstanding. He received a well-deserved standing ovation at the end of his address.

Sport and socialization a necessity in sunny Florida!

The afternoon adjourned after the business meeting, and members were able to play golf, tennis, paddleboard in Winter Park, or just relax at the resort. Congratulations to the winners of the golf tournament (Drs. Hopkins, Rasmussen, Hurd, and Flora) and the tennis tournament (Dr. Ted Lee)!

Everyone convened at the outside terrace for the evening “Mojito Night in the Caribbean” reception, sharing good times, cocktails, and hors d’oeuvres. Proceeds from each ticket sold helped support Surgeons Helping Advance Research and Education (SHARE).

Tomorrow looks to be an excellent conclusion to a well-planned and very well-executed meeting. Kudos, and large thanks, to the SGS leadership.

3/23/15, Day 2 at SGS

Surgeons from 17 countries converge

The first day of the SGS scientific sessions was another energetic and interactive day. Sixteen new SGS members were recognized and welcomed in the main conference hall. Dr. Charles Rardin presented a brief overview and some basic statistics related to this year’s meeting—the largest ever in the history of SGS. A total of 401 attendees representing 17 countries are here in Orlando for SGS 2015! 

In the first scientific session, oral presentations touched on the subjects of preoperative dexamethasone use, vaginal packing, surgical site infections, and a new treatment modality for fecal incontinence. An excellent technique video on laparoscopic ureterolysis by Dr. Cara King then followed, in which she demonstrated excellent surgical skills with amazingly clear anatomy. Her video was recognized later in the day with a well-deserved award—congratulations! 

 

A short break in the exhibit hall allowed for mingling with other attendees, many of whom have been active on social media surrounding the meeting, and for visiting the booths of the industry sponsors. The second scientific session then picked up where the first left off, with more scientifically sound research presented on such topics as mechanical bowel preparation use in laparoscopy and pelvic floor disorders in women with gynecologic malignancies.

No room for fads in gyn surgery

Dr. David Grimes, a true leader in our field, provided an exceptional keynote address, “Is Teaching Evidence-Based Surgery Possible?" He shared his expertise of evidence-based medicine, and described (in sometimes very comical but always stimulating and provocative terms) the need for incorporating evidence-based surgery in gynecology. He urged us to strive to do best by our patients by applying evidenced-based practices rather than following fads and gizmos.

Gyn surgery training: Have we reached a “perfect storm”?

The afternoon brought with it a panel discussion on "Teaching the Next Generation of GYN Surgeons," with Dr. Hal Lawrence moderating and Dr. Mark Walters and Dr. Dee Fenner serving as panelists. They discussed the future of ObGyn residency training in great detail: increasing subspecialization, a stable birth rate, declining hysterectomy rates, increasing safety and quality monitoring, and increased access to data and informed consumers. All of these trends were highlighted as reasons for a perfect storm in gynecologic surgery training. In addition, the panel presented some surprising statistics: 

• The majority of hysterectomies in the United States are being done by surgeons who perform less than 1 per month.
• The higher volume surgeons provide higher value and tend to utilize more minimally invasive approaches.

Videofest!

The scientific day concluded with a videofest that included complex robotic, laparoscopic, hysteroscopic, cystoscopic, and vaginal surgeries, demonstrating the surgical talents and ingenuity of SGS members.

Simultaneously, the Fellows’ Pelvic Research Network (FPRN) met to update their ongoing projects and to review new proposals. The meeting sought to unite FPRMS and MIS fellows to conduct multicenter studies. This was an enlightening and engaging session, which should give everyone great hope to see the creativity and energy of the next generation of researchers.

A grounder for attendees

All in attendance were treated to a unique, eye-opening, motivational, and very moving talk by Professor (and Sir) Ajay Rane, MD, PhD from Australia on female genital mutilation. He stressed the importance of respecting women for who they are, not what they do.

“My idea of feminism is applauding a woman who gives birth. Celebrate women for who they are," he said. He highlighted the work being done by his team in Australia and India, and urged everyone in attendance to become more aware of the staggering statistics and reality of female genital mutilation.

The jam-packed day wrapped with the awards ceremony in the main hall. Lifelong mentors were honored by their mentees and SGS President Dr. Stephen Metz and Scientific Program Chair Dr. Charles Rardin presented various awards to those who had submitted and presented novel and groundbreaking research.

One last surprise

The President’s Reception in the exhibit hall was lively, with meeting sponsors, colleagues, and friends in attendance. And, of course, a visit from special guest! (Thanks to SGS Fellow Christina Saad, MD @XtinaSaad for the pic!)

See you all tomorrow for another educational, enlightening, and spirited day at #SGS2015! 

3/22/15. DAY 1 AT SGS

A focus on evidence-based medicine

Strong analytic skills (of your own research as well as the published literature) translates to better patient care, was the underlying theme of the opening postgraduate course here in Orlando, Florida, for day 1 of the 41st annual meeting of the Society of Gynecologic Surgeons.

Building on the success of last year’s course on evidence-based medicine (EBM), Dr. Vivian Sung and Dr. Ike Rahn put together an amazing team to review and apply the principles of so-called EBM, a workshop that was in part sponsored by ABOG.

A quick introduction to EBM principles by Dr. Thomas Wheeler was followed by small break-out groups, where attendees used the PICO-DD model to define a Population, Intervention, Comparator, Outcomes, Duration, and study Design. Further talks focused on the benefits and caveats of randomized controlled trials (RCTs), surrogate and intermediate outcomes, and systematic reviews and meta-analyses.

Dr. Ethan Balk cautioned us to consider the costly and underpowered RCT, and lack of generalizability needed to define rigorous study inclusion and outcome criteria. Dr. Sung then pointed out that, while the perfect surrogate outcome would allow us to shorten study lengths (and save money), the seduction of association and causation can lead to some questionable conclusions.

 

When using a clinical practice guideline, Dr. Miles Murphy indicated that a systematic review needs to be included, although a meta-analysis is not always required. The poor quality and paucity of RCTs for most patient populations is what limits us.

Dr. Rahn gave an excellent presentation on subgroup analysis, recommending to attendees that they perform these analyses cautiously, describe which groups are analyzed, and have statistical back-up for power and P value calculations.

Dr. Kristen Matteson then spoke about interpreting the literature on screening and diagnostic tests, giving a thorough but understandable review of the basics of statistics. Dr. John Wong rounded out the course, suggesting that because RCTs are expensive and comprise less than 5% of published studies, the analysis of observational studies as RCTs would allow us to better inform our patients and our colleagues on the best treatments, using patient-centered outcomes, efficacy data, and multiple providers. He urged us all to be more skeptical and ask critical questions when dealing with evidence in medicine.

Sharpening ultrasonography skills

Simultaneously, others attended a hands-on learning course on comprehensive pelvic floor ultrasonography, including transperineal, endovaginal, and endoanal imaging, organized by Dr. Abbas Shobeiri.

Tips for the difficult hysterectomy

Dr. Ted Lee (with help from Drs. Arnold P. Advincula, Rosanne Kho, and Matthew Seidhoff) prepared a surgical tutorial on laparoscopic, robotic, and vaginal strategies and techniques for approaching the difficult hysterectomy. The course was phenomenal, as described by many of the members fortunate enough to learn some of the tips and tricks demonstrated by the master surgeons.

Training for the NIH application process

Following the postgraduate courses, Dr. Katherine Hartmann led an “NIH Application Training Camp,” an offering supported by SGS research donations and a generous donation from Dr. Holly Richter. Dr. Hartmann provided in-depth insight into the world of NIH grant funding and provided background prep for a K or R award application. A mock NIH application study section, in which two actual applications were reviewed, demystified the process of grant review (and rejection). 

A social end to day 1

To end the first day, a welcome reception was held where residents, fellows, and attendings from different fields of ObGyn mingled and shared drinks, stories, and good laughs.

The "social" activities continue on social media for the rest of the conference. Follow #SGS2015, @gynsurgery, @obgmanagement, and @sukrantmehta for more!

Over the past several years, there has been increasing amounts of research documenting the caregiving challenges that accompany the day-to-day parenting of a child with special health needs and/or chronic medical conditions. Children who are diagnosed with emotional and behavioral problems (ranging from attention-deficit/hyperactivity disorder (ADHD) to autism – which also can be considered chronic conditions), can pose parenting challenges for even the most healthy, supportive, and committed parents. From the point of receiving a diagnosis to daily management of the range of symptoms and attempting to coordinate care with various providers, the emotional stress experienced by caregivers can be quite burdensome and may affect the functioning of the entire family. In an effort to achieve successful treatment outcomes for the child, it’s important to be mindful of this emotional stress and provide parents with tools to foster their own wellness and mental health while mitigating the risk for them developing their own health concerns.

Case summary

 

Bridget is a 10-year-old girl who presents with her single mother for a psychiatric consultation. Since early childhood, Bridget has demonstrated an array of behaviors that have affected her ability to engage with others socially; she was thought to be a temperamentally shy and sensitive toddler, and in elementary school, her mother describes the emergence of odd mental status changes and accompanying motor movements that were later diagnosed as complex-partial epilepsy. Since this diagnosis at the age of 6 years, despite receiving various antiepileptic treatment, Bridget has continued to present with an intractable seizure disorder. She is now prescribed a combination of benzodiazepines, cannabinoids, and other antiepileptic agents, but still has marked functional impairments. Behaviorally, it appears that Bridget has experienced some regression over the years and has been recently tested to have low-average intelligence and a neurocognitive profile characterized by attentional difficulties, executive impairments, and significant processing deficits.

Because of her complicated presentation, Bridget has been unable to attend school-based academic instruction, and her escalating levels of generalized worry have limited her ability to reliably interact with individuals outside of the family. These challenges also have posed difficulties for providers to perform thorough evaluations and provide Bridget with psychosocial interventions to address her anxiety and self-regulatory deficits. All in all, Bridget is a diagnostically complicated young girl. Her mother wishes to “figure things out,” and acknowledges having trouble managing her daughter’s increasingly defiant and unpredictable behaviors. In the past, setting limits and placing stress on Bridget have been thought to be etiologically related to seizure onset. Additionally, Bridget’s mother has been unable to find her own employment while providing care for her daughter and reports that financially, she isn’t sure how she can make ends meet while providing Bridget with medical marijuana. Bridget’s mother’s composure during the evaluation is applauded (particularly when her daughter’s defiant actions are readily appreciated), but she admits to feeling “exhausted.”

Discussion

Bridget’s case illustrates not only the complexities in attempting to understand and diagnose multifaceted neuropsychiatric phenomena, but also the struggles experienced by families who are challenged economically, socially, psychologically, and emotionally as a result of their child’s difficulties. Although caregiving and parenting is rife with rewarding opportunities for many family members, the provision of such nurturance can undoubtedly place parents at risk for significant hardships. Studies have demonstrated that caregiving demands are associated with poor health outcomes in adult caregivers (Ann. Behav. Med. 1997;19:110-6), and maternal cortisol levels in mothers of older children with autism were found to be significantly lower than normal and the hormonal dysregulation was associated with their child’s behavioral profile. Such findings are similar to those recognized in combat soldiers and others who experience enduring psychological distress (J. Autism Dev. Disord. 2010; 40:457-69).

Upon meeting with Bridget, it became clear that her mother required additional support and services to help care for her daughter’s difficult needs. Through seeking a diagnosis for her daughter, Bridget’s mother also was pursuing an understanding of her daughter’s strengths and struggles, and looking to partner with a provider who might be able to help her navigate the often complicated system of care. By gathering a comprehensive family history (assessing what mom’s vulnerabilities may be for developing her own mental health issues) and thoroughly assessing her current functioning with the Adult Self-Report and the Parenting Stress Index, as a provider, I was better informed to offer family-based treatment recommendations. Through self-reporting, Bridget’s mother endorsed her own mood complaints, occasional substance use, and a constellation of anxiety-based difficulties. We had a thoughtful discussion pertaining to elements of grief, fears, and guilt, which helped to lay the foundation for later exploring how Bridget may best be cared for in the future (such as residential placement). Bridget’s mother shared that she initially felt like a failure for seeking help and not “being able to parent” her daughter; supportive techniques were used to provide her with reassurance and validation.

 

Using Bridget’s mother’s strengths (resiliency, being a strong advocate for her daughter), other recommendations also were offered to help her to more effectively parent her child and avoid burnout. Not inclusive of suggestions directed towards Bridget individually, these recommendations included:

• Having mom seek her own psychotherapeutic and psychiatric care. Goals of her treatment would be to support her own wellness (through exercise, mindfulness, engagement in positive activities) and focus on developing healthy relationships. By getting her own anxiety under control, assessing her own parenting and coping styles, and additionally obtaining psychoeducation about anxiety disorders in children, mom is primed to develop more successful ways to address Bridget’s defiance and avoid enabling her daughter’s excessive worry while encouraging her to be more socially active.

• Finding respite providers for Bridget. Then mom has more opportunities to seek employment and participate in other out-of-the-home activities.

• Developing a relationship with the school district. This way mom can obtain appropriate supports and accommodations for Bridget to be educated outside the home.

• Exploring community resources through local agencies. This would help mom plan for the future, examine possible sources of financial support, and perhaps most importantly, obtain a treatment team leader and care coordinator.

• Enhancing social supports. This can be done via connections to local support groups.

Clinical pearl

It’s not surprising that parents of children with special needs experience high levels of stress. Be aware of how such stress can affect a parent’s ability to care for their child, and be mindful that a child’s wellness can be significantly mediated by parental wellness and health. When designing treatment plans, routinely assess family caregivers’ stress levels (including that of siblings and fathers) and evaluate other indicators of stress (such as sleep disturbances, weight change, apathy, and expression of negative emotion). Advocate for programs and systems of care that can address both parental and child mental health issues in a coordinated manner that also enhances family cohesion, reduces social isolation, and decreases parental marginalization.

Dr. Dickerson, a child and adolescent psychiatrist, is an assistant professor of psychiatry at the University of Vermont, Burlington. He is the director of the university’s autism diagnostic clinic. Contact Dr. Dickerson at [email protected].

Over the past several years, there has been increasing amounts of research documenting the caregiving challenges that accompany the day-to-day parenting of a child with special health needs and/or chronic medical conditions. Children who are diagnosed with emotional and behavioral problems (ranging from attention-deficit/hyperactivity disorder (ADHD) to autism – which also can be considered chronic conditions), can pose parenting challenges for even the most healthy, supportive, and committed parents. From the point of receiving a diagnosis to daily management of the range of symptoms and attempting to coordinate care with various providers, the emotional stress experienced by caregivers can be quite burdensome and may affect the functioning of the entire family. In an effort to achieve successful treatment outcomes for the child, it’s important to be mindful of this emotional stress and provide parents with tools to foster their own wellness and mental health while mitigating the risk for them developing their own health concerns.

Case summary

 

Bridget is a 10-year-old girl who presents with her single mother for a psychiatric consultation. Since early childhood, Bridget has demonstrated an array of behaviors that have affected her ability to engage with others socially; she was thought to be a temperamentally shy and sensitive toddler, and in elementary school, her mother describes the emergence of odd mental status changes and accompanying motor movements that were later diagnosed as complex-partial epilepsy. Since this diagnosis at the age of 6 years, despite receiving various antiepileptic treatment, Bridget has continued to present with an intractable seizure disorder. She is now prescribed a combination of benzodiazepines, cannabinoids, and other antiepileptic agents, but still has marked functional impairments. Behaviorally, it appears that Bridget has experienced some regression over the years and has been recently tested to have low-average intelligence and a neurocognitive profile characterized by attentional difficulties, executive impairments, and significant processing deficits.

Because of her complicated presentation, Bridget has been unable to attend school-based academic instruction, and her escalating levels of generalized worry have limited her ability to reliably interact with individuals outside of the family. These challenges also have posed difficulties for providers to perform thorough evaluations and provide Bridget with psychosocial interventions to address her anxiety and self-regulatory deficits. All in all, Bridget is a diagnostically complicated young girl. Her mother wishes to “figure things out,” and acknowledges having trouble managing her daughter’s increasingly defiant and unpredictable behaviors. In the past, setting limits and placing stress on Bridget have been thought to be etiologically related to seizure onset. Additionally, Bridget’s mother has been unable to find her own employment while providing care for her daughter and reports that financially, she isn’t sure how she can make ends meet while providing Bridget with medical marijuana. Bridget’s mother’s composure during the evaluation is applauded (particularly when her daughter’s defiant actions are readily appreciated), but she admits to feeling “exhausted.”

Discussion

Bridget’s case illustrates not only the complexities in attempting to understand and diagnose multifaceted neuropsychiatric phenomena, but also the struggles experienced by families who are challenged economically, socially, psychologically, and emotionally as a result of their child’s difficulties. Although caregiving and parenting is rife with rewarding opportunities for many family members, the provision of such nurturance can undoubtedly place parents at risk for significant hardships. Studies have demonstrated that caregiving demands are associated with poor health outcomes in adult caregivers (Ann. Behav. Med. 1997;19:110-6), and maternal cortisol levels in mothers of older children with autism were found to be significantly lower than normal and the hormonal dysregulation was associated with their child’s behavioral profile. Such findings are similar to those recognized in combat soldiers and others who experience enduring psychological distress (J. Autism Dev. Disord. 2010; 40:457-69).

Upon meeting with Bridget, it became clear that her mother required additional support and services to help care for her daughter’s difficult needs. Through seeking a diagnosis for her daughter, Bridget’s mother also was pursuing an understanding of her daughter’s strengths and struggles, and looking to partner with a provider who might be able to help her navigate the often complicated system of care. By gathering a comprehensive family history (assessing what mom’s vulnerabilities may be for developing her own mental health issues) and thoroughly assessing her current functioning with the Adult Self-Report and the Parenting Stress Index, as a provider, I was better informed to offer family-based treatment recommendations. Through self-reporting, Bridget’s mother endorsed her own mood complaints, occasional substance use, and a constellation of anxiety-based difficulties. We had a thoughtful discussion pertaining to elements of grief, fears, and guilt, which helped to lay the foundation for later exploring how Bridget may best be cared for in the future (such as residential placement). Bridget’s mother shared that she initially felt like a failure for seeking help and not “being able to parent” her daughter; supportive techniques were used to provide her with reassurance and validation.

 

Using Bridget’s mother’s strengths (resiliency, being a strong advocate for her daughter), other recommendations also were offered to help her to more effectively parent her child and avoid burnout. Not inclusive of suggestions directed towards Bridget individually, these recommendations included:

• Having mom seek her own psychotherapeutic and psychiatric care. Goals of her treatment would be to support her own wellness (through exercise, mindfulness, engagement in positive activities) and focus on developing healthy relationships. By getting her own anxiety under control, assessing her own parenting and coping styles, and additionally obtaining psychoeducation about anxiety disorders in children, mom is primed to develop more successful ways to address Bridget’s defiance and avoid enabling her daughter’s excessive worry while encouraging her to be more socially active.

• Finding respite providers for Bridget. Then mom has more opportunities to seek employment and participate in other out-of-the-home activities.

• Developing a relationship with the school district. This way mom can obtain appropriate supports and accommodations for Bridget to be educated outside the home.

• Exploring community resources through local agencies. This would help mom plan for the future, examine possible sources of financial support, and perhaps most importantly, obtain a treatment team leader and care coordinator.

• Enhancing social supports. This can be done via connections to local support groups.

Clinical pearl

It’s not surprising that parents of children with special needs experience high levels of stress. Be aware of how such stress can affect a parent’s ability to care for their child, and be mindful that a child’s wellness can be significantly mediated by parental wellness and health. When designing treatment plans, routinely assess family caregivers’ stress levels (including that of siblings and fathers) and evaluate other indicators of stress (such as sleep disturbances, weight change, apathy, and expression of negative emotion). Advocate for programs and systems of care that can address both parental and child mental health issues in a coordinated manner that also enhances family cohesion, reduces social isolation, and decreases parental marginalization.

Dr. Dickerson, a child and adolescent psychiatrist, is an assistant professor of psychiatry at the University of Vermont, Burlington. He is the director of the university’s autism diagnostic clinic. Contact Dr. Dickerson at [email protected].

Over the past several years, there has been increasing amounts of research documenting the caregiving challenges that accompany the day-to-day parenting of a child with special health needs and/or chronic medical conditions. Children who are diagnosed with emotional and behavioral problems (ranging from attention-deficit/hyperactivity disorder (ADHD) to autism – which also can be considered chronic conditions), can pose parenting challenges for even the most healthy, supportive, and committed parents. From the point of receiving a diagnosis to daily management of the range of symptoms and attempting to coordinate care with various providers, the emotional stress experienced by caregivers can be quite burdensome and may affect the functioning of the entire family. In an effort to achieve successful treatment outcomes for the child, it’s important to be mindful of this emotional stress and provide parents with tools to foster their own wellness and mental health while mitigating the risk for them developing their own health concerns.

Case summary

 

Bridget is a 10-year-old girl who presents with her single mother for a psychiatric consultation. Since early childhood, Bridget has demonstrated an array of behaviors that have affected her ability to engage with others socially; she was thought to be a temperamentally shy and sensitive toddler, and in elementary school, her mother describes the emergence of odd mental status changes and accompanying motor movements that were later diagnosed as complex-partial epilepsy. Since this diagnosis at the age of 6 years, despite receiving various antiepileptic treatment, Bridget has continued to present with an intractable seizure disorder. She is now prescribed a combination of benzodiazepines, cannabinoids, and other antiepileptic agents, but still has marked functional impairments. Behaviorally, it appears that Bridget has experienced some regression over the years and has been recently tested to have low-average intelligence and a neurocognitive profile characterized by attentional difficulties, executive impairments, and significant processing deficits.

Because of her complicated presentation, Bridget has been unable to attend school-based academic instruction, and her escalating levels of generalized worry have limited her ability to reliably interact with individuals outside of the family. These challenges also have posed difficulties for providers to perform thorough evaluations and provide Bridget with psychosocial interventions to address her anxiety and self-regulatory deficits. All in all, Bridget is a diagnostically complicated young girl. Her mother wishes to “figure things out,” and acknowledges having trouble managing her daughter’s increasingly defiant and unpredictable behaviors. In the past, setting limits and placing stress on Bridget have been thought to be etiologically related to seizure onset. Additionally, Bridget’s mother has been unable to find her own employment while providing care for her daughter and reports that financially, she isn’t sure how she can make ends meet while providing Bridget with medical marijuana. Bridget’s mother’s composure during the evaluation is applauded (particularly when her daughter’s defiant actions are readily appreciated), but she admits to feeling “exhausted.”

Discussion

Bridget’s case illustrates not only the complexities in attempting to understand and diagnose multifaceted neuropsychiatric phenomena, but also the struggles experienced by families who are challenged economically, socially, psychologically, and emotionally as a result of their child’s difficulties. Although caregiving and parenting is rife with rewarding opportunities for many family members, the provision of such nurturance can undoubtedly place parents at risk for significant hardships. Studies have demonstrated that caregiving demands are associated with poor health outcomes in adult caregivers (Ann. Behav. Med. 1997;19:110-6), and maternal cortisol levels in mothers of older children with autism were found to be significantly lower than normal and the hormonal dysregulation was associated with their child’s behavioral profile. Such findings are similar to those recognized in combat soldiers and others who experience enduring psychological distress (J. Autism Dev. Disord. 2010; 40:457-69).

Upon meeting with Bridget, it became clear that her mother required additional support and services to help care for her daughter’s difficult needs. Through seeking a diagnosis for her daughter, Bridget’s mother also was pursuing an understanding of her daughter’s strengths and struggles, and looking to partner with a provider who might be able to help her navigate the often complicated system of care. By gathering a comprehensive family history (assessing what mom’s vulnerabilities may be for developing her own mental health issues) and thoroughly assessing her current functioning with the Adult Self-Report and the Parenting Stress Index, as a provider, I was better informed to offer family-based treatment recommendations. Through self-reporting, Bridget’s mother endorsed her own mood complaints, occasional substance use, and a constellation of anxiety-based difficulties. We had a thoughtful discussion pertaining to elements of grief, fears, and guilt, which helped to lay the foundation for later exploring how Bridget may best be cared for in the future (such as residential placement). Bridget’s mother shared that she initially felt like a failure for seeking help and not “being able to parent” her daughter; supportive techniques were used to provide her with reassurance and validation.

 

Using Bridget’s mother’s strengths (resiliency, being a strong advocate for her daughter), other recommendations also were offered to help her to more effectively parent her child and avoid burnout. Not inclusive of suggestions directed towards Bridget individually, these recommendations included:

• Having mom seek her own psychotherapeutic and psychiatric care. Goals of her treatment would be to support her own wellness (through exercise, mindfulness, engagement in positive activities) and focus on developing healthy relationships. By getting her own anxiety under control, assessing her own parenting and coping styles, and additionally obtaining psychoeducation about anxiety disorders in children, mom is primed to develop more successful ways to address Bridget’s defiance and avoid enabling her daughter’s excessive worry while encouraging her to be more socially active.

• Finding respite providers for Bridget. Then mom has more opportunities to seek employment and participate in other out-of-the-home activities.

• Developing a relationship with the school district. This way mom can obtain appropriate supports and accommodations for Bridget to be educated outside the home.

• Exploring community resources through local agencies. This would help mom plan for the future, examine possible sources of financial support, and perhaps most importantly, obtain a treatment team leader and care coordinator.

• Enhancing social supports. This can be done via connections to local support groups.

Clinical pearl

It’s not surprising that parents of children with special needs experience high levels of stress. Be aware of how such stress can affect a parent’s ability to care for their child, and be mindful that a child’s wellness can be significantly mediated by parental wellness and health. When designing treatment plans, routinely assess family caregivers’ stress levels (including that of siblings and fathers) and evaluate other indicators of stress (such as sleep disturbances, weight change, apathy, and expression of negative emotion). Advocate for programs and systems of care that can address both parental and child mental health issues in a coordinated manner that also enhances family cohesion, reduces social isolation, and decreases parental marginalization.

Dr. Dickerson, a child and adolescent psychiatrist, is an assistant professor of psychiatry at the University of Vermont, Burlington. He is the director of the university’s autism diagnostic clinic. Contact Dr. Dickerson at [email protected].

Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.

The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have  worse outcomes.

Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.

The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.

The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.

But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).

The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).

Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.

In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).

MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).

MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.

“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”

Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.

On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.

Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46.

Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.

The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have  worse outcomes.

Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.

The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.

The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.

But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).

The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).

Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.

In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).

MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).

MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.

“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”

Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.

On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.

Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46.

Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.

The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have  worse outcomes.

Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.

The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.

The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.

But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).

The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).

Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.

In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).

MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).

MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.

“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”

Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.

On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.

Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46.

Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.

The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.

And they believe this finding will aid the development of vaccine candidates that are already under investigation.

“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.

“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”

Dr Beeson and his colleagues described their research in Immunity.

The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.

Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.

Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.

To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.

This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.

The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.

Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.

The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.

“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”

Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.

The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.

And they believe this finding will aid the development of vaccine candidates that are already under investigation.

“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.

“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”

Dr Beeson and his colleagues described their research in Immunity.

The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.

Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.

Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.

To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.

This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.

The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.

Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.

The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.

“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”

Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.

The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.

And they believe this finding will aid the development of vaccine candidates that are already under investigation.

“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.

“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”

Dr Beeson and his colleagues described their research in Immunity.

The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.

Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.

Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.

To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.

This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.

The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.

Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.

The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.

“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”

Clozapine is a second‐generation antipsychotic (SGA) medication that was developed in 1959, introduced to Europe in 1971, and withdrawn from the market in 1975 due to associated concerns for potentially fatal agranulocytosis. In 1989, the US Food and Drug Administration (FDA) approved use of clozapine for the management of treatment‐resistant schizophrenia, under strict parameters for complete blood count (CBC) monitoring. Clozapine has since gained an additional FDA indication for reducing suicidal behavior in patients with schizophrenia and schizoaffective disorder,[1, 2, 3] and displayed superiority to both first generation antipsychotics and other SGA agents in reducing symptom burden.[2, 4, 5]

Clozapine's clinical benefits include lowering mortality in schizophrenia,[6] reducing deaths from ischemic heart disease,[7] curtailing substance use in individuals with psychotic disorders,[8] increasing rates of independent living and meaningful occupational activity, and reducing psychiatric hospitalizations and need for involuntary treatment.[9] Because schizophrenia, itself, is associated with a 15‐ to 20‐year decrease in average lifespan,[10] these benefits of clozapine are particularly salient. Yet the mechanism by which clozapine mitigates otherwise‐refractory psychotic symptoms is a conundrum. Structurally a tricyclic dibenzodiazepine, clozapine has relatively little effect on the dopamine D2 receptor, which has classically been thought to mediate the treatment effect of antipsychotics.[11, 12]

The unique nature of clozapine extends to its adverse effect profile. A significant percentage of patients who discontinue clozapine (17%35.4%) cite medical complications, the most common being seizures, constipation, sedation, and neutropenia.[13, 14] Yet several studies, including the landmark Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study, have found that patients were more likely to adhere to clozapine therapy than to other antipsychotics.[2, 15] In the CATIE study, 44% of subjects taking clozapine continued the medication for 18 months, compared to 29% of individuals on olanzapine, 14% on risperidone, and 7% on quetiapine. Median time until discontinuation of clozapine was 10.5 months, significantly longer than for quetiapine (2.8 months) and olanzapine (2.7 months).[2] Because patients who experience clozapine‐related medical complications are likely to present first to the primary care or general hospital setting, internists must be aware of potential iatrogenic effects, and of their implications for psychiatric and medical care. Using case examples, we will examine both common and serious complications associated with clozapine, and discuss recommendations for management, including indications for clozapine discontinuation.

NEUROLOGICAL

Case Vignette 1

Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.

Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]

Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]

CARDIAC

Case Vignette 2

Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 10³/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.

Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]

Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]

Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]

Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.

GASTROINTESTINAL

Case Vignette 3

Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.

Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.

Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]

Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.

HEMATOLOGIC

Case Vignette 4

Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm³ and absolute neutrophil count (ANC) of 4700/mm³. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm³ and ANC to 2200/mm³. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm³ and ANC at 790/mm³. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm³ and ANC >1500/mm³. An alternate psychotropic medication was initiated several weeks thereafter.

Neutropenia (white blood cell count 3000/mm³) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm³.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]

In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]

The most feared complication of clozapine remains agranulocytosis, defined as ANC500/mm³,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]

The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]

Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm³.[21, 41]

ADDITIONAL COMPLICATIONS (METABOLIC, RENAL, URINARY)

Moderate to marked weight gain occurs in over 50% of patients treated with clozapine, with average gains of nearly 10% body weight.[43] In a 10‐year follow‐up study of patients treated with clozapine, Henderson et al. reported an average weight gain of 13 kg, with 34% percent of studied patients developing diabetes mellitus. Metabolic side effects of second‐generation antipsychotics, including clozapine, are a well‐documented and troubling phenomenon.[44] Limited evidence supports use of metformin, alongside behavioral therapy, for concerns related to glucose dysregulation.[45] Some patients have also experienced weight loss with adjunctive topiramate use, particularly if they have also suffered seizures.[46]

Urinary incontinence and nocturnal enuresis are both associated with clozapine, but are likely under‐reported because of patient and provider embarrassment; providers also may not think to ask about these specific symptoms. First‐line treatment for nocturnal enuresis is to limit fluids in the evening. Desmopressin has a controversial role in treating nocturnal enuresis owing to its risk of hyponatremia; appropriate monitoring should be implemented if this agent is used.[18]

Clozapine has been associated with acute interstitial nephritis (AIN), although this is thought to be a relatively rare side effect. Drug‐induced AIN typically appears soon after initiation and presents with the clinical triad of rash, fever, and eosinophilia. Given that weekly CBC is mandatory in the initiation phase, eosinophilia is easily detectible and may serve as a marker for potential AIN.[47]

Sialorrhea, particularly during sleep, is a bothersome condition affecting up to one‐third of patients who take clozapine.[48] Although clozapine is strongly anticholinergic, its agonist activity at the M4 muscarinic receptor and antagonism of the alpha‐2 adrenergic receptor are postulated as the mechanisms underlying hypersalivation. Sialorrhea is frequently seen early in treatment and does not appear to be dose dependent.[48] Excessive salivation is typically managed with behavioral interventions (eg, utilizing towels or other absorbent materials on top of bedding). If hypersalivation occurs during the day, chewing sugar‐free gum may increase the rate of swallowing and make symptoms less bothersome. If this does not provide adequate relief, practitioners may consider use of atropine 1% solution administered directly to the oral cavity.[49]

DRUG‐DRUG INTERACTIONS

For hospitalists, who must frequently alter existing medications or add new ones, awareness of potential drug‐drug interactions is crucial. Clozapine is metabolized by the cytochrome p450 system, with predominant metabolism through the isoenzymes 1A2, 3A4, and 2D6.[50] Common medications that induce clozapine metabolism (thereby decreasing clozapine levels) include phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and corticosteroids. Conversely, stopping these medications after long‐term therapy will raise clozapine levels. Substances that inhibit clozapine metabolism (thereby increasing clozapine levels) include ciprofloxacin, erythromycin, clarithromycin, fluvoxamine, fluoxetine, paroxetine, protease inhibitors, verapamil, and grapefruit juice. We recommend caution when concurrently administering other agents that increase risk for agranulocytosis, including carbamazepine, trimethoprim‐sulfamethoxazole, sulfasalazine, and tricyclic antidepressants.

Cigarette smoking decreases clozapine blood levels by induction of CYP1A2. Patients require a 10% to 30% reduction to clozapine dose during periods of smoking cessation, including when smoking is stopped during inpatient hospitalization.[51] Nicotine replacement therapy does not induce CYP1A2 and therefore does not have a compensatory effect on clozapine levels. On discharge or resumption of smoking, patients may require an increase of their dose of clozapine to maintain adequate antipsychotic effect.

SUMMARY OF RECOMMENDATIONS

Medical complications are cited as the cause in 20% of clozapine discontinuations; most commonly, these include seizures, severe constipation, somnolence, and neutropenia. Given the high risk of psychiatric morbidity posed by discontinuation, we recommend managing mild‐moderate symptoms and side effects while continuing the drug, when possible (Table 1). We encourage hospitalists to confer with the patient's psychiatrist or the inpatient psychiatry consultation service when making changes to clozapine therapy. Specific recommendations are as follows:

1. We advocate withholding clozapine administration pending medical optimization for several conditions, including: small‐bowel obstruction, neuroleptic malignant syndrome, venous thromboembolism, diabetic ketoacidosis, or hyperosmolar coma.
2. Clinical scenarios requiring acute discontinuation of clozapine include agranulocytosis and myocarditis. Successful rechallenge with clozapine has been described after both conditions; at the same time, given the high morbidity and mortality of myocarditis and agranulocytosis, re‐initiation of clozapine requires an extensive risk‐benefit discussion with the patient and family, informed consent, and, in the case of agranulocytosis, approval from the national clozapine registry (Table 2).
3. Although adjunctive therapy with filgrastim was initially thought to permit a clozapine rechallenge in patients with a history of agranulocytosis, case reports on this strategy have been equivocal, and further research is necessary to determine the most effective strategy for management.

Table 1.Recommended Monitoring Parameters During Clozapine Use

	Clinical Lab/Study	Frequency of Monitoring
Cardiac	Electrocardiogram	Baseline, 24 weeks after initiation, every 6 months thereafter
	Cardiac enzymes (eg, troponin I) echocardiogram	No standard guidelines, unless clinically indicated
Hematologic	Complete blood count with differential	Baseline, then weekly 26 weeks, then every 2 weeks 26 weeks, then every 4 weeks thereafter
Metabolic	Body mass index; circumference of waist	Baseline, then every 3 to 6 months
	Fasting glucose	Baseline, then every 6 months
Fasting lipid panel	Baseline, then yearly
Neurologic	Electroencephalogram	No standard guidelines, unless clinically indicated
Vital signs	Heart rate, blood pressure, temperature	Baseline and at each follow‐up visit

Table 2.Medical Indications for Altering Clozapine Therapy

Requires Acute Clozapine Discontinuation*	Clozapine Interruption During Management	Does Not Typically Require Clozapine Discontinuation
NOTE: Abbreviations: ANC, absolute neutrophil count. *Limited case reports suggest possibility of rechallenge under close multidisciplinary supervision. Requires symptomatic management, consideration of more frequent monitoring or clozapine dose adjustment and weighing risks‐benefits of continuation or discontinuation.
Agranulocytosis (ANC1.0 109/mm3)	Diabetic complications (eg, ketoacidosis, hyperosmolar coma)	Constipation
Cardiomyopathy (severe)	Gastrointestinal obstruction, ileus	Diabetes mellitus
Myocarditis	Neuroleptic malignant syndrome	Gastroesophageal Reflux
	Venous thromboembolism	Hyperlipidemia
Hypertension
Orthostatic hypotension
Sedation
Seizures
Sialorrhea
Sinus tachycardia
Urinary changes (eg, enuresis, incontinence)
Weight gain

CONCLUSION

Clozapine has been a very successful treatment for patients with schizophrenia who have failed other antipsychotic therapies. However, fears of potential side effects and frequent monitoring have limited its use and led to unnecessary discontinuation. To mitigate risk for serious complications, we hope to increase hospitalists' awareness of prevention, monitoring, and treatment of side effects, and to promote comfort with circumstances that warrant continuation or discontinuation of clozapine (Table 3). The hospitalist plays a crucial role in managing these complications as well as conveying information and recommendations to primary care providers; as such, their familiarity with the medication is essential for proper management of individuals who take clozapine.

Table 3.Take‐Home Points

Take‐Home Points
1. Clozapine is the gold standard for treatment‐resistant schizophrenia; however, its use is limited by side effects, many of which can be successfully treated by internists.
2. There are few indications for discontinuing clozapine (myocarditis, small‐bowel obstruction, agranulocytosis). The psychiatry service should be consulted in the event that clozapine is discontinued.
3. Seizures are not an indication for discontinuing clozapine; instead, we recommend adding an antiepileptic drug.
4. All second‐generation antipsychotics are associated with diabetes mellitus and significant weight gain. Clozapine is more highly associated with metabolic side effects than many other medications in this class.
5. Sedation, sialorrhea, and constipation are common and can be managed pharmacologically and with behavioral interventions.

Disclosure: Nothing to report.

Clozapine is a second‐generation antipsychotic (SGA) medication that was developed in 1959, introduced to Europe in 1971, and withdrawn from the market in 1975 due to associated concerns for potentially fatal agranulocytosis. In 1989, the US Food and Drug Administration (FDA) approved use of clozapine for the management of treatment‐resistant schizophrenia, under strict parameters for complete blood count (CBC) monitoring. Clozapine has since gained an additional FDA indication for reducing suicidal behavior in patients with schizophrenia and schizoaffective disorder,[1, 2, 3] and displayed superiority to both first generation antipsychotics and other SGA agents in reducing symptom burden.[2, 4, 5]

Clozapine's clinical benefits include lowering mortality in schizophrenia,[6] reducing deaths from ischemic heart disease,[7] curtailing substance use in individuals with psychotic disorders,[8] increasing rates of independent living and meaningful occupational activity, and reducing psychiatric hospitalizations and need for involuntary treatment.[9] Because schizophrenia, itself, is associated with a 15‐ to 20‐year decrease in average lifespan,[10] these benefits of clozapine are particularly salient. Yet the mechanism by which clozapine mitigates otherwise‐refractory psychotic symptoms is a conundrum. Structurally a tricyclic dibenzodiazepine, clozapine has relatively little effect on the dopamine D2 receptor, which has classically been thought to mediate the treatment effect of antipsychotics.[11, 12]

The unique nature of clozapine extends to its adverse effect profile. A significant percentage of patients who discontinue clozapine (17%35.4%) cite medical complications, the most common being seizures, constipation, sedation, and neutropenia.[13, 14] Yet several studies, including the landmark Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study, have found that patients were more likely to adhere to clozapine therapy than to other antipsychotics.[2, 15] In the CATIE study, 44% of subjects taking clozapine continued the medication for 18 months, compared to 29% of individuals on olanzapine, 14% on risperidone, and 7% on quetiapine. Median time until discontinuation of clozapine was 10.5 months, significantly longer than for quetiapine (2.8 months) and olanzapine (2.7 months).[2] Because patients who experience clozapine‐related medical complications are likely to present first to the primary care or general hospital setting, internists must be aware of potential iatrogenic effects, and of their implications for psychiatric and medical care. Using case examples, we will examine both common and serious complications associated with clozapine, and discuss recommendations for management, including indications for clozapine discontinuation.

NEUROLOGICAL

Case Vignette 1

Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.

Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]

Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]

CARDIAC

Case Vignette 2

Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 10³/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.

Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]

Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]

Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]

Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.

GASTROINTESTINAL

Case Vignette 3

Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.

Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.

Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]

Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.

HEMATOLOGIC

Case Vignette 4

Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm³ and absolute neutrophil count (ANC) of 4700/mm³. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm³ and ANC to 2200/mm³. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm³ and ANC at 790/mm³. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm³ and ANC >1500/mm³. An alternate psychotropic medication was initiated several weeks thereafter.

Neutropenia (white blood cell count 3000/mm³) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm³.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]

In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]

The most feared complication of clozapine remains agranulocytosis, defined as ANC500/mm³,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]

The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]

Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm³.[21, 41]

ADDITIONAL COMPLICATIONS (METABOLIC, RENAL, URINARY)

Moderate to marked weight gain occurs in over 50% of patients treated with clozapine, with average gains of nearly 10% body weight.[43] In a 10‐year follow‐up study of patients treated with clozapine, Henderson et al. reported an average weight gain of 13 kg, with 34% percent of studied patients developing diabetes mellitus. Metabolic side effects of second‐generation antipsychotics, including clozapine, are a well‐documented and troubling phenomenon.[44] Limited evidence supports use of metformin, alongside behavioral therapy, for concerns related to glucose dysregulation.[45] Some patients have also experienced weight loss with adjunctive topiramate use, particularly if they have also suffered seizures.[46]

Urinary incontinence and nocturnal enuresis are both associated with clozapine, but are likely under‐reported because of patient and provider embarrassment; providers also may not think to ask about these specific symptoms. First‐line treatment for nocturnal enuresis is to limit fluids in the evening. Desmopressin has a controversial role in treating nocturnal enuresis owing to its risk of hyponatremia; appropriate monitoring should be implemented if this agent is used.[18]

Clozapine has been associated with acute interstitial nephritis (AIN), although this is thought to be a relatively rare side effect. Drug‐induced AIN typically appears soon after initiation and presents with the clinical triad of rash, fever, and eosinophilia. Given that weekly CBC is mandatory in the initiation phase, eosinophilia is easily detectible and may serve as a marker for potential AIN.[47]

Sialorrhea, particularly during sleep, is a bothersome condition affecting up to one‐third of patients who take clozapine.[48] Although clozapine is strongly anticholinergic, its agonist activity at the M4 muscarinic receptor and antagonism of the alpha‐2 adrenergic receptor are postulated as the mechanisms underlying hypersalivation. Sialorrhea is frequently seen early in treatment and does not appear to be dose dependent.[48] Excessive salivation is typically managed with behavioral interventions (eg, utilizing towels or other absorbent materials on top of bedding). If hypersalivation occurs during the day, chewing sugar‐free gum may increase the rate of swallowing and make symptoms less bothersome. If this does not provide adequate relief, practitioners may consider use of atropine 1% solution administered directly to the oral cavity.[49]

DRUG‐DRUG INTERACTIONS

For hospitalists, who must frequently alter existing medications or add new ones, awareness of potential drug‐drug interactions is crucial. Clozapine is metabolized by the cytochrome p450 system, with predominant metabolism through the isoenzymes 1A2, 3A4, and 2D6.[50] Common medications that induce clozapine metabolism (thereby decreasing clozapine levels) include phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and corticosteroids. Conversely, stopping these medications after long‐term therapy will raise clozapine levels. Substances that inhibit clozapine metabolism (thereby increasing clozapine levels) include ciprofloxacin, erythromycin, clarithromycin, fluvoxamine, fluoxetine, paroxetine, protease inhibitors, verapamil, and grapefruit juice. We recommend caution when concurrently administering other agents that increase risk for agranulocytosis, including carbamazepine, trimethoprim‐sulfamethoxazole, sulfasalazine, and tricyclic antidepressants.

Cigarette smoking decreases clozapine blood levels by induction of CYP1A2. Patients require a 10% to 30% reduction to clozapine dose during periods of smoking cessation, including when smoking is stopped during inpatient hospitalization.[51] Nicotine replacement therapy does not induce CYP1A2 and therefore does not have a compensatory effect on clozapine levels. On discharge or resumption of smoking, patients may require an increase of their dose of clozapine to maintain adequate antipsychotic effect.

SUMMARY OF RECOMMENDATIONS

Medical complications are cited as the cause in 20% of clozapine discontinuations; most commonly, these include seizures, severe constipation, somnolence, and neutropenia. Given the high risk of psychiatric morbidity posed by discontinuation, we recommend managing mild‐moderate symptoms and side effects while continuing the drug, when possible (Table 1). We encourage hospitalists to confer with the patient's psychiatrist or the inpatient psychiatry consultation service when making changes to clozapine therapy. Specific recommendations are as follows:

1. We advocate withholding clozapine administration pending medical optimization for several conditions, including: small‐bowel obstruction, neuroleptic malignant syndrome, venous thromboembolism, diabetic ketoacidosis, or hyperosmolar coma.
2. Clinical scenarios requiring acute discontinuation of clozapine include agranulocytosis and myocarditis. Successful rechallenge with clozapine has been described after both conditions; at the same time, given the high morbidity and mortality of myocarditis and agranulocytosis, re‐initiation of clozapine requires an extensive risk‐benefit discussion with the patient and family, informed consent, and, in the case of agranulocytosis, approval from the national clozapine registry (Table 2).
3. Although adjunctive therapy with filgrastim was initially thought to permit a clozapine rechallenge in patients with a history of agranulocytosis, case reports on this strategy have been equivocal, and further research is necessary to determine the most effective strategy for management.

Table 1.Recommended Monitoring Parameters During Clozapine Use

	Clinical Lab/Study	Frequency of Monitoring
Cardiac	Electrocardiogram	Baseline, 24 weeks after initiation, every 6 months thereafter
	Cardiac enzymes (eg, troponin I) echocardiogram	No standard guidelines, unless clinically indicated
Hematologic	Complete blood count with differential	Baseline, then weekly 26 weeks, then every 2 weeks 26 weeks, then every 4 weeks thereafter
Metabolic	Body mass index; circumference of waist	Baseline, then every 3 to 6 months
	Fasting glucose	Baseline, then every 6 months
Fasting lipid panel	Baseline, then yearly
Neurologic	Electroencephalogram	No standard guidelines, unless clinically indicated
Vital signs	Heart rate, blood pressure, temperature	Baseline and at each follow‐up visit

Table 2.Medical Indications for Altering Clozapine Therapy

Requires Acute Clozapine Discontinuation*	Clozapine Interruption During Management	Does Not Typically Require Clozapine Discontinuation
NOTE: Abbreviations: ANC, absolute neutrophil count. *Limited case reports suggest possibility of rechallenge under close multidisciplinary supervision. Requires symptomatic management, consideration of more frequent monitoring or clozapine dose adjustment and weighing risks‐benefits of continuation or discontinuation.
Agranulocytosis (ANC1.0 109/mm3)	Diabetic complications (eg, ketoacidosis, hyperosmolar coma)	Constipation
Cardiomyopathy (severe)	Gastrointestinal obstruction, ileus	Diabetes mellitus
Myocarditis	Neuroleptic malignant syndrome	Gastroesophageal Reflux
	Venous thromboembolism	Hyperlipidemia
Hypertension
Orthostatic hypotension
Sedation
Seizures
Sialorrhea
Sinus tachycardia
Urinary changes (eg, enuresis, incontinence)
Weight gain

CONCLUSION

Clozapine has been a very successful treatment for patients with schizophrenia who have failed other antipsychotic therapies. However, fears of potential side effects and frequent monitoring have limited its use and led to unnecessary discontinuation. To mitigate risk for serious complications, we hope to increase hospitalists' awareness of prevention, monitoring, and treatment of side effects, and to promote comfort with circumstances that warrant continuation or discontinuation of clozapine (Table 3). The hospitalist plays a crucial role in managing these complications as well as conveying information and recommendations to primary care providers; as such, their familiarity with the medication is essential for proper management of individuals who take clozapine.

Table 3.Take‐Home Points

Take‐Home Points
1. Clozapine is the gold standard for treatment‐resistant schizophrenia; however, its use is limited by side effects, many of which can be successfully treated by internists.
2. There are few indications for discontinuing clozapine (myocarditis, small‐bowel obstruction, agranulocytosis). The psychiatry service should be consulted in the event that clozapine is discontinued.
3. Seizures are not an indication for discontinuing clozapine; instead, we recommend adding an antiepileptic drug.
4. All second‐generation antipsychotics are associated with diabetes mellitus and significant weight gain. Clozapine is more highly associated with metabolic side effects than many other medications in this class.
5. Sedation, sialorrhea, and constipation are common and can be managed pharmacologically and with behavioral interventions.

Disclosure: Nothing to report.

Clozapine is a second‐generation antipsychotic (SGA) medication that was developed in 1959, introduced to Europe in 1971, and withdrawn from the market in 1975 due to associated concerns for potentially fatal agranulocytosis. In 1989, the US Food and Drug Administration (FDA) approved use of clozapine for the management of treatment‐resistant schizophrenia, under strict parameters for complete blood count (CBC) monitoring. Clozapine has since gained an additional FDA indication for reducing suicidal behavior in patients with schizophrenia and schizoaffective disorder,[1, 2, 3] and displayed superiority to both first generation antipsychotics and other SGA agents in reducing symptom burden.[2, 4, 5]

Clozapine's clinical benefits include lowering mortality in schizophrenia,[6] reducing deaths from ischemic heart disease,[7] curtailing substance use in individuals with psychotic disorders,[8] increasing rates of independent living and meaningful occupational activity, and reducing psychiatric hospitalizations and need for involuntary treatment.[9] Because schizophrenia, itself, is associated with a 15‐ to 20‐year decrease in average lifespan,[10] these benefits of clozapine are particularly salient. Yet the mechanism by which clozapine mitigates otherwise‐refractory psychotic symptoms is a conundrum. Structurally a tricyclic dibenzodiazepine, clozapine has relatively little effect on the dopamine D2 receptor, which has classically been thought to mediate the treatment effect of antipsychotics.[11, 12]

The unique nature of clozapine extends to its adverse effect profile. A significant percentage of patients who discontinue clozapine (17%35.4%) cite medical complications, the most common being seizures, constipation, sedation, and neutropenia.[13, 14] Yet several studies, including the landmark Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study, have found that patients were more likely to adhere to clozapine therapy than to other antipsychotics.[2, 15] In the CATIE study, 44% of subjects taking clozapine continued the medication for 18 months, compared to 29% of individuals on olanzapine, 14% on risperidone, and 7% on quetiapine. Median time until discontinuation of clozapine was 10.5 months, significantly longer than for quetiapine (2.8 months) and olanzapine (2.7 months).[2] Because patients who experience clozapine‐related medical complications are likely to present first to the primary care or general hospital setting, internists must be aware of potential iatrogenic effects, and of their implications for psychiatric and medical care. Using case examples, we will examine both common and serious complications associated with clozapine, and discuss recommendations for management, including indications for clozapine discontinuation.

NEUROLOGICAL

Case Vignette 1

Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.

Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]

Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]

CARDIAC

Case Vignette 2

Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 10³/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.

Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]

Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]

Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]

Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.

GASTROINTESTINAL

Case Vignette 3

Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.

Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.

Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]

Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.

HEMATOLOGIC

Case Vignette 4

Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm³ and absolute neutrophil count (ANC) of 4700/mm³. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm³ and ANC to 2200/mm³. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm³ and ANC at 790/mm³. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm³ and ANC >1500/mm³. An alternate psychotropic medication was initiated several weeks thereafter.

Neutropenia (white blood cell count 3000/mm³) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm³.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]

In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]

The most feared complication of clozapine remains agranulocytosis, defined as ANC500/mm³,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]

The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]

Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm³.[21, 41]

ADDITIONAL COMPLICATIONS (METABOLIC, RENAL, URINARY)

Moderate to marked weight gain occurs in over 50% of patients treated with clozapine, with average gains of nearly 10% body weight.[43] In a 10‐year follow‐up study of patients treated with clozapine, Henderson et al. reported an average weight gain of 13 kg, with 34% percent of studied patients developing diabetes mellitus. Metabolic side effects of second‐generation antipsychotics, including clozapine, are a well‐documented and troubling phenomenon.[44] Limited evidence supports use of metformin, alongside behavioral therapy, for concerns related to glucose dysregulation.[45] Some patients have also experienced weight loss with adjunctive topiramate use, particularly if they have also suffered seizures.[46]

Urinary incontinence and nocturnal enuresis are both associated with clozapine, but are likely under‐reported because of patient and provider embarrassment; providers also may not think to ask about these specific symptoms. First‐line treatment for nocturnal enuresis is to limit fluids in the evening. Desmopressin has a controversial role in treating nocturnal enuresis owing to its risk of hyponatremia; appropriate monitoring should be implemented if this agent is used.[18]

Clozapine has been associated with acute interstitial nephritis (AIN), although this is thought to be a relatively rare side effect. Drug‐induced AIN typically appears soon after initiation and presents with the clinical triad of rash, fever, and eosinophilia. Given that weekly CBC is mandatory in the initiation phase, eosinophilia is easily detectible and may serve as a marker for potential AIN.[47]

Sialorrhea, particularly during sleep, is a bothersome condition affecting up to one‐third of patients who take clozapine.[48] Although clozapine is strongly anticholinergic, its agonist activity at the M4 muscarinic receptor and antagonism of the alpha‐2 adrenergic receptor are postulated as the mechanisms underlying hypersalivation. Sialorrhea is frequently seen early in treatment and does not appear to be dose dependent.[48] Excessive salivation is typically managed with behavioral interventions (eg, utilizing towels or other absorbent materials on top of bedding). If hypersalivation occurs during the day, chewing sugar‐free gum may increase the rate of swallowing and make symptoms less bothersome. If this does not provide adequate relief, practitioners may consider use of atropine 1% solution administered directly to the oral cavity.[49]

DRUG‐DRUG INTERACTIONS

For hospitalists, who must frequently alter existing medications or add new ones, awareness of potential drug‐drug interactions is crucial. Clozapine is metabolized by the cytochrome p450 system, with predominant metabolism through the isoenzymes 1A2, 3A4, and 2D6.[50] Common medications that induce clozapine metabolism (thereby decreasing clozapine levels) include phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and corticosteroids. Conversely, stopping these medications after long‐term therapy will raise clozapine levels. Substances that inhibit clozapine metabolism (thereby increasing clozapine levels) include ciprofloxacin, erythromycin, clarithromycin, fluvoxamine, fluoxetine, paroxetine, protease inhibitors, verapamil, and grapefruit juice. We recommend caution when concurrently administering other agents that increase risk for agranulocytosis, including carbamazepine, trimethoprim‐sulfamethoxazole, sulfasalazine, and tricyclic antidepressants.

Cigarette smoking decreases clozapine blood levels by induction of CYP1A2. Patients require a 10% to 30% reduction to clozapine dose during periods of smoking cessation, including when smoking is stopped during inpatient hospitalization.[51] Nicotine replacement therapy does not induce CYP1A2 and therefore does not have a compensatory effect on clozapine levels. On discharge or resumption of smoking, patients may require an increase of their dose of clozapine to maintain adequate antipsychotic effect.

SUMMARY OF RECOMMENDATIONS

Medical complications are cited as the cause in 20% of clozapine discontinuations; most commonly, these include seizures, severe constipation, somnolence, and neutropenia. Given the high risk of psychiatric morbidity posed by discontinuation, we recommend managing mild‐moderate symptoms and side effects while continuing the drug, when possible (Table 1). We encourage hospitalists to confer with the patient's psychiatrist or the inpatient psychiatry consultation service when making changes to clozapine therapy. Specific recommendations are as follows:

1. We advocate withholding clozapine administration pending medical optimization for several conditions, including: small‐bowel obstruction, neuroleptic malignant syndrome, venous thromboembolism, diabetic ketoacidosis, or hyperosmolar coma.
2. Clinical scenarios requiring acute discontinuation of clozapine include agranulocytosis and myocarditis. Successful rechallenge with clozapine has been described after both conditions; at the same time, given the high morbidity and mortality of myocarditis and agranulocytosis, re‐initiation of clozapine requires an extensive risk‐benefit discussion with the patient and family, informed consent, and, in the case of agranulocytosis, approval from the national clozapine registry (Table 2).
3. Although adjunctive therapy with filgrastim was initially thought to permit a clozapine rechallenge in patients with a history of agranulocytosis, case reports on this strategy have been equivocal, and further research is necessary to determine the most effective strategy for management.

Table 1.Recommended Monitoring Parameters During Clozapine Use

	Clinical Lab/Study	Frequency of Monitoring
Cardiac	Electrocardiogram	Baseline, 24 weeks after initiation, every 6 months thereafter
	Cardiac enzymes (eg, troponin I) echocardiogram	No standard guidelines, unless clinically indicated
Hematologic	Complete blood count with differential	Baseline, then weekly 26 weeks, then every 2 weeks 26 weeks, then every 4 weeks thereafter
Metabolic	Body mass index; circumference of waist	Baseline, then every 3 to 6 months
	Fasting glucose	Baseline, then every 6 months
Fasting lipid panel	Baseline, then yearly
Neurologic	Electroencephalogram	No standard guidelines, unless clinically indicated
Vital signs	Heart rate, blood pressure, temperature	Baseline and at each follow‐up visit

Table 2.Medical Indications for Altering Clozapine Therapy

Requires Acute Clozapine Discontinuation*	Clozapine Interruption During Management	Does Not Typically Require Clozapine Discontinuation
NOTE: Abbreviations: ANC, absolute neutrophil count. *Limited case reports suggest possibility of rechallenge under close multidisciplinary supervision. Requires symptomatic management, consideration of more frequent monitoring or clozapine dose adjustment and weighing risks‐benefits of continuation or discontinuation.
Agranulocytosis (ANC1.0 109/mm3)	Diabetic complications (eg, ketoacidosis, hyperosmolar coma)	Constipation
Cardiomyopathy (severe)	Gastrointestinal obstruction, ileus	Diabetes mellitus
Myocarditis	Neuroleptic malignant syndrome	Gastroesophageal Reflux
	Venous thromboembolism	Hyperlipidemia
Hypertension
Orthostatic hypotension
Sedation
Seizures
Sialorrhea
Sinus tachycardia
Urinary changes (eg, enuresis, incontinence)
Weight gain

CONCLUSION

Clozapine has been a very successful treatment for patients with schizophrenia who have failed other antipsychotic therapies. However, fears of potential side effects and frequent monitoring have limited its use and led to unnecessary discontinuation. To mitigate risk for serious complications, we hope to increase hospitalists' awareness of prevention, monitoring, and treatment of side effects, and to promote comfort with circumstances that warrant continuation or discontinuation of clozapine (Table 3). The hospitalist plays a crucial role in managing these complications as well as conveying information and recommendations to primary care providers; as such, their familiarity with the medication is essential for proper management of individuals who take clozapine.

Table 3.Take‐Home Points

Take‐Home Points
1. Clozapine is the gold standard for treatment‐resistant schizophrenia; however, its use is limited by side effects, many of which can be successfully treated by internists.
2. There are few indications for discontinuing clozapine (myocarditis, small‐bowel obstruction, agranulocytosis). The psychiatry service should be consulted in the event that clozapine is discontinued.
3. Seizures are not an indication for discontinuing clozapine; instead, we recommend adding an antiepileptic drug.
4. All second‐generation antipsychotics are associated with diabetes mellitus and significant weight gain. Clozapine is more highly associated with metabolic side effects than many other medications in this class.
5. Sedation, sialorrhea, and constipation are common and can be managed pharmacologically and with behavioral interventions.

Disclosure: Nothing to report.

Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.

Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.

Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.

“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.

“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”

TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.

Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.

“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.

He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.

The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).

On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.

Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).

And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.

“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.

“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”

Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.

Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.

Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.

“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.

“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”

TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.

Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.

“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.

He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.

The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).

On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.

Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).

And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.

“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.

“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”

Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.

Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.

Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.

“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.

“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”

TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.

Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.

“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.

He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.

The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).

On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.

Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).

And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.

“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.

“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”

After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.

MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.

The researchers reported these findings in NEJM.

“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.

“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”

Scans reveal brain swelling

In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.

Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.

The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.

In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.

“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”

After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.

MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.

The researchers reported these findings in NEJM.

“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.

“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”

Scans reveal brain swelling

In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.

Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.

The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.

In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.

“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”

After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.

MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.

The researchers reported these findings in NEJM.

“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.

“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”

Scans reveal brain swelling

In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.

Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.

The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.

In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.

“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”