How to prevent adverse drug events

Medication errors due to system-, provider-, or patient-related factors contribute significantly to increased costs, adverse drug events (ADEs), and morbidity and mortality.¹ One study found >60% of ADEs that led to hospitalization could have been prevented by strategies such as adequate monitoring or appropriate prescribing.² Psychiatrists have an opportunity to reduce rates of ADEs; however, the possibility of disease symptoms overlapping with these adverse events is 1 of many obstacles prescribing clinicians face.¹ Prescribers also must contend with adverse effects of polypharmacy, which are common among psychiatric patients. Patient-related factors of concern include:

• seeing multiple prescribers
• medication nonadherence
• failure to communicate use of herbal or over-the-counter products
• lack of insight
• comorbid medical and psychiatric diagnoses, such as dementia.¹

This article highlights potential ADEs and major medication safety concerns that may contribute to morbidity and mortality among patients taking psychotropics. Although many factors are beyond the prescribing clinician’s control—such as medication dispensing and administration errors—psychiatrists can substantially reduce ADEs. We will cover potential adverse events associated with key medications or medication classes, drug interactions with potentially devastating consequences, and strategies to minimize risks of ADEs, including enhanced awareness and monitoring (Table 1).

Table 1

How to avoid ADEs with psychotropics

Prescription drug overdose

Each year, unintentional drug overdoses account for >20,000 deaths in the United States.³ Prescription medications, particularly opioid analgesics, have contributed to the doubling of overdose mortality rates in recent years. A recent study reported that nearly 50% of unintentional drug overdose deaths were associated with psychotropics and one-third of these deaths were associated with benzodiazepines, many of which were not prescribed to the individual.⁴

The risk of mortality from intentional drug overdose also must be assessed. Tricyclic antidepressants (TCAs) are a particularly lethal class of medications in suicide attempts and may result in arrhythmias, coma, seizures, respiratory failure, and death.⁵ Venlafaxine and mirtazapine are associated with greater risk of death and toxicity in overdose, respectively, than selective serotonin reuptake inhibitors (SSRIs).⁶ Lithium toxicity in overdose may lead to bradycardia, seizure, coma, hyperventilation, serotonin syndrome, respiratory failure, or death.⁵ The risk of death with lithium or benzodiazepine monotherapy is low when these agents are taken as prescribed. However, prescribers must exercise caution when these agents are used in combination. Interactions involving drugs with a narrow therapeutic index—such as lithium and TCAs—are more likely to be clinically significant because small increases in drug concentration can lead to serious adverse effects or death. See Related Resources for a review article on appropriate use and monitoring of lithium.

Drug-drug interactions

Many Americans take multiple prescription and nonprescription drugs, and psychiatric patients are more likely than other individuals to have more complex medication regimens.⁷ This can result in polypharmacy and drug-drug interactions (DDIs), which can lead to undesired medication effects and serious, potentially fatal ADEs.

Pharmacokinetic interactions typically affect drug concentrations and occur when 1 drug interferes with the absorption, distribution, metabolism, or excretion of another drug. Many common pharmacokinetic interactions involve the liver cytochrome P450 (CYP) system, which is responsible for metabolizing many medications.⁸ DDIs can occur when CYP enzymes are modified by inhibitors or inducers, which can decrease or increase drug clearance, respectively. Table 2 ^5,7,9 provides examples of common CYP450 substrates, inhibitors, and inducers. Polymorphisms in the pharmacogenetics of CYP450 also can affect overall drug clearance and the impact of DDIs.⁸

Pharmacodynamic interactions are caused by additive or competing effects of multiple drugs. The most serious of these involve medications that increase a patient’s risk of serotonin syndrome or neuroleptic malignant syndrome (NMS); both are medical emergencies that require immediate hospitalization.

Although any medication with serotonergic activity can induce serotonin syndrome, combinations of serotonergic drugs in particular are associated with increased risk.¹⁰ Serotonin syndrome is characterized by hyperthermia, altered muscle tone, altered mental status, and autonomic instability; rhabdomyolysis and disseminated intravascular coagulation are potential lethal complications.¹⁰ A high index of suspicion can help clinicians rapidly detect serotonin syndrome, discontinue offending agents, and initiate supportive treatments.

NMS is a life-threatening complication of antipsychotics characterized by fever, delirium, muscle rigidity, autonomic instability, and abnormal laboratory findings that include elevated white blood count and increased creatinine kinase from muscle injury. In early stages, NMS may be mistaken for extrapyramidal symptoms. Although NMS can occur with any antipsychotic as monotherapy, additive antidopaminergic effects increase the risk. Patients with a compromised CNS as a result of mental retardation, traumatic brain injury, or metabolic abnormalities also are at increased risk of developing NMS.¹¹

Other pharmacodynamic interactions involve medications that may have additive effects on prolonging QTc intervals. For example, TCAs are pro-arrhythmic and have quinidine-like effects, which can cause cardiac conduction abnormalities and prolonged PR and QTc intervals.¹² Employ routine ECG monitoring when prescribing multiple medications known to cause QTc prolongation, such as TCAs (Table 3).^13,14 The Arizona Center for Education and Research on Therapeutics (www.azcert.org) provides a searchable list of QT-prolonging drugs (see Related Resources).

Medications also can interact with food, disease states, and herbal supplements. Alcohol interacts with many CNS-active medications, including many psychotropics. Patients taking benzodiazepines may experience oversedation and respiratory depression from alcohol’s additive sedating effects.⁵ Advise patients to limit their alcohol intake while taking CNS-depressing psychotropics such as benzodiazepines, antipsychotics, and some antidepressants. Monoamine oxidase inhibitors (MAOIs) and tyramine-containing food—such as cheese, beer, preserved meat, and soy sauce—can lead to a dangerous hypertensive crisis that requires immediate medical intervention to prevent life-threatening complications.⁵ Hypertensive crisis may be more significant in patients who have pre-existing hypertension. Finally, herbal supplements also can interact with medications. Patients who take St. John’s wort for depressive symptoms might not realize that it can reduce the efficacy of other drugs or increase their risk of serotonin syndrome.⁹

Table 2

Cytochrome P450 substrates, inhibitors, and inducers

Table 3

Psychotropics associated with QT prolongation

Black-box warnings

“Black-box” warnings issued by the FDA are included in the package insert to highlight a medication’s risks of dangerous and potentially lethal adverse effects. Table 4 highlights current black-box warnings for various psychotropics.^5,14-16

Antidepressants and suicide. All medications with antidepressant indications carry a black-box warning for risk of suicidal ideation and behavior in children, adolescents, and young adults during the early months of medication therapy. This includes not only SSRIs and serotonin-norepinephrine reuptake inhibitors, but also anticonvulsants and atypical antipsychotics indicated for treating mood disorders. Monitor young patients carefully and advise family members to alert clinicians of any signs of suicidality or unusual behavior.

Lamotrigine and aseptic meningitis. Aseptic meningitis—inflammation of the meninges that is not caused by bacteria—is a rare but serious adverse effect of lamotrigine. Symptoms include headache, fever, stiff neck, nausea and vomiting, delirium, rash, and sensitivity to light.⁵ Forty cases of aseptic meningitis in children and adults were reported over 15 years, representing <.01% of all lamotrigine prescriptions.⁵ Most of these patients required hospitalization, but symptoms resolved after lamotrigine was discontinued. Prompt identification and management of aseptic meningitis are necessary to prevent permanent brain damage and death. Other complications of aseptic meningitis include long-term neurologic sequelae such as cognitive impairment, seizure disorders, and behavioral disturbances.

Table 4

Which psychotropics carry ‘black-box’ warnings?

Other complications

Hematologic effects. All classes of psychotropics carry a risk (1 to 2 cases per year per 100,00 patients) of serious hematologic complications, including neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura, and anemia.¹⁷ Agranulocytosis has been associated most commonly with clozapine, carbamazepine, and typical antipsychotics.¹⁷ SSRIs, which are widely prescribed, are associated with increased risk of bruising and bleeding. Patients with bleeding or platelet disorders are at an increased risk for these complications.¹⁷

Seizures. Several classes of psychotropics are associated with an increased risk of seizures. Among antipsychotics, clozapine and chlorpromazine are the most seizurogenic.¹⁸ Among antidepressants, bupropion and clomipramine are most likely to lower seizure thresholds.¹⁸ Psychotropics’ seizure-inducing effects are dose-related. Vulnerability to seizures while taking psychotropics is related to having a history of epilepsy or brain injury.¹⁸ Seizures also can occur when benzodiazepines or anticonvulsants are withdrawn too quickly.

Heat stroke. Although a rare occurrence, psychotropics with anticholinergic side effects can contribute to heat stroke. Older patients are particularly vulnerable to the risk of body temperature dysregulation.¹⁹

Ketoacidosis and hyperosmolar coma. Medication-related deaths have occurred as a result of ketoacidosis and hyperosmolar coma associated with atypical antipsychotics. These hyperglycemia-related fatalities are most likely with clozapine and olanzapine.²⁰

Hip fractures and falls. Geriatric patients are vulnerable to falls and resultant hip fractures related to use of TCAs, SSRIs, benzodiazepines, and antipsychotics. This is not a trivial matter; hip fractures increase the mortality rate by 12% to 20% in the year after the injury.²¹ The risk of falls is related to sedation, orthostatic hypotension, arrhythmias, and confusion associated with psychotropics.^21,22

Akathisia and suicide. Unrecognized or undertreated akathisia is most commonly associated with antipsychotics, but also can occur with SSRIs. Although akathisia is commonly thought of as a motor syndrome of restlessness, patients may find the less-recognized psychic symptoms of increased inner turmoil and hallucinations just as distressing. This complex of symptoms is associated with an increased risk of suicide.²³ If discontinuing the offending agent is not feasible, akathisia can be treated with beta blockers, benzodiazepines, or anticholinergics.²⁴

Hepatotoxicity. Hepatotoxicity from psychotropics occurs in only a small percentage of patients, and can range from transient elevations in liver enzymes to fulminant liver failure. Adverse hepatic effects may be a manifestation of a hypersensitivity reaction accompanied by rash and eosinophilia.²⁵ MAOIs and TCAs can cause cholestatic liver injury, whereas nefazodone has been associated with fulminant liver failure. Other psychotropics—including SSRIs, antipsychotics, benzodiazepines, and older antiepileptics—can cause negative hepatic effects but rarely are associated with acute liver failure.^25,26 Although few medications can cause complete liver failure on their own, hepatotoxicity from medications may precipitate severe, potentially fatal outcomes in patients with underlying liver diseases such as hepatitis and cirrhosis. Additive hepatotoxicity from multiple medications also can be problematic. Although psychotropic-induced hepatotoxicity is rare, assess psychotropic doses in patients with liver dysfunction, because drug clearance may be altered, which increases the risk for other serious adverse events.²⁵

Suicide assessment is key

Ongoing monitoring for current or developing suicidal ideation is an important strategy to prevent medication-related mortality in patients vulnerable to self-harm. Initial assessments and follow-up appointments should include a detailed inquiry about suicidal ideations, plans, and behaviors. Patients taking medications that carry black-box warnings for suicide risk should be seen frequently during the first few months of treatment. Patients receiving medications that are lethal in overdose (eg, lithium and TCAs) should be carefully screened for suicide risk. Prescribe medications in limited quantities or arrange for a family member to monitor the patient if necessary. Patients with a history of suicide attempts and current suicide plans may require close observation and initiating medications while hospitalized.

Other prevention strategies

Prescribing psychotropics in a manner that promotes mental well being while minimizing negative outcomes can be challenging. By developing a personal formulary of drugs commonly encountered and prescribed in their practice, psychiatrists can increase their awareness of serious safety concerns, potential DDIs, and appropriate use based on available literature.^7,27

Medication histories and drug reconciliation—comparing a patient’s medication orders to all of the medications the patient has been taking—can help clinicians avoid making inappropriate dose adjustments, duplicating therapy, or prescribing medications patients previously have failed or did not tolerate. Establishing a collaborative practice environment with physicians, pharmacists, nurses, and social workers can minimize medication errors and risk of adverse outcomes by increasing communication regarding the patient’s treatment.⁷

Computerized drug databases and other electronic resources and consultation with pharmacists can help prescribers identify, avoid, and manage clinically significant DDIs.²⁷ Medications could interact with other drugs as long as their effects persist in the body, which could be days to months after the drug is discontinued. Future research may lead to tools to identify patient pharmacogenetic profiles.

Recognizing psychotropic DDIs and adverse effects remains a challenge because of the complexity of the affected organ, the brain. Clinicians should be vigilant to changes in a patient’s presentation because they may be a manifestation of a medication side effect.⁷ Appropriate therapeutic drug monitoring should occur on a routine, scheduled basis. Closer monitoring may be necessary with dose changes, potential DDIs, signs and symptoms of toxicity/efficacy failure, and renal or hepatic function changes.

Lastly, patients’ education and involvement in their health care may increase their awareness, responsibility, and medication adherence. For challenging patients, family involvement and “eyes on” medication administration can increase adherence and prevent psychotropic misuse.

Related Resources

• Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval and/or induce Torsades de Pointes ventricular arrhythmia. www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
• Cates ME, Sims PJ. Therapeutic drug management of lithium. Am J Pharm Educ. 2005;69(5):88.
• Wren P, Frizzell LA, Keltner NL, et al. Three potentially fatal adverse effects of psychotropic medications. Perspect Psychiatr Care. 2003;39(2):75-81.
• Bishop JR, Bishop DL. How to prevent serotonin syndrome from drug-drug interactions. Current Psychiatry. 2011;10(3):81-83.

Drug Brand Names

• Amantadine • Symmetrel
• Amiodarone • Cordarone, Pacerone
• Amitriptyline • Elavil
• Amphetamine/dextroamphetamine • Adderall, others
• Aprepitant • Emend
• Aripiprazole • Abilify
• Asenapine • Saphris
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol, others
• Chloral hydrate • Somnote
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Diltiazem • Cardia, others
• Diphenhydramine • Benadryl, others
• Doxepin • Sinequan, Silenor
• Duloxetine • Cymbalta
• Erythromycin • Ery-Tab, others
• Fluconazole • Diflucan
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Galantamine • Razadyne
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Imatinib • Gleevec
• Imipramine • Tofranil
• Isoniazid • Nydrazid, others
• Ketoconazole • Nizoral, others
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Methadone • Dolophine, Methadose
• Methylphenidate/ dexmethylphenidate • Ritalin, others
• Mirtazapine • Remeron
• Nafcillin • Nafcil, others
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxcarbazepine • Trileptal
• Paliperidone • Invega
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenobarbital • Luminal, others
• Phenytoin • Dilantin
• Protriptyline • Vivactil
• Quetiapine • Seroquel
• Rifampin • Rifadin, others
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trimethoprim/Sulfamethoxazole • Bactrim, Septra
• Trimipramine • Surmontil
• Valproic acid • Depakote, others
• Venlafaxine • Effexor
• Verapamil • Calan, others
• Ziprasidone • Geodon

Disclosure

Drs. Yu and Bostwick report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca, Pfizer Inc, and Sunovion Pharmaceuticals.

Medication errors due to system-, provider-, or patient-related factors contribute significantly to increased costs, adverse drug events (ADEs), and morbidity and mortality.¹ One study found >60% of ADEs that led to hospitalization could have been prevented by strategies such as adequate monitoring or appropriate prescribing.² Psychiatrists have an opportunity to reduce rates of ADEs; however, the possibility of disease symptoms overlapping with these adverse events is 1 of many obstacles prescribing clinicians face.¹ Prescribers also must contend with adverse effects of polypharmacy, which are common among psychiatric patients. Patient-related factors of concern include:

• seeing multiple prescribers
• medication nonadherence
• failure to communicate use of herbal or over-the-counter products
• lack of insight
• comorbid medical and psychiatric diagnoses, such as dementia.¹

This article highlights potential ADEs and major medication safety concerns that may contribute to morbidity and mortality among patients taking psychotropics. Although many factors are beyond the prescribing clinician’s control—such as medication dispensing and administration errors—psychiatrists can substantially reduce ADEs. We will cover potential adverse events associated with key medications or medication classes, drug interactions with potentially devastating consequences, and strategies to minimize risks of ADEs, including enhanced awareness and monitoring (Table 1).

Table 1

How to avoid ADEs with psychotropics

Prescription drug overdose

Each year, unintentional drug overdoses account for >20,000 deaths in the United States.³ Prescription medications, particularly opioid analgesics, have contributed to the doubling of overdose mortality rates in recent years. A recent study reported that nearly 50% of unintentional drug overdose deaths were associated with psychotropics and one-third of these deaths were associated with benzodiazepines, many of which were not prescribed to the individual.⁴

The risk of mortality from intentional drug overdose also must be assessed. Tricyclic antidepressants (TCAs) are a particularly lethal class of medications in suicide attempts and may result in arrhythmias, coma, seizures, respiratory failure, and death.⁵ Venlafaxine and mirtazapine are associated with greater risk of death and toxicity in overdose, respectively, than selective serotonin reuptake inhibitors (SSRIs).⁶ Lithium toxicity in overdose may lead to bradycardia, seizure, coma, hyperventilation, serotonin syndrome, respiratory failure, or death.⁵ The risk of death with lithium or benzodiazepine monotherapy is low when these agents are taken as prescribed. However, prescribers must exercise caution when these agents are used in combination. Interactions involving drugs with a narrow therapeutic index—such as lithium and TCAs—are more likely to be clinically significant because small increases in drug concentration can lead to serious adverse effects or death. See Related Resources for a review article on appropriate use and monitoring of lithium.

Drug-drug interactions

Many Americans take multiple prescription and nonprescription drugs, and psychiatric patients are more likely than other individuals to have more complex medication regimens.⁷ This can result in polypharmacy and drug-drug interactions (DDIs), which can lead to undesired medication effects and serious, potentially fatal ADEs.

Pharmacokinetic interactions typically affect drug concentrations and occur when 1 drug interferes with the absorption, distribution, metabolism, or excretion of another drug. Many common pharmacokinetic interactions involve the liver cytochrome P450 (CYP) system, which is responsible for metabolizing many medications.⁸ DDIs can occur when CYP enzymes are modified by inhibitors or inducers, which can decrease or increase drug clearance, respectively. Table 2 ^5,7,9 provides examples of common CYP450 substrates, inhibitors, and inducers. Polymorphisms in the pharmacogenetics of CYP450 also can affect overall drug clearance and the impact of DDIs.⁸

Pharmacodynamic interactions are caused by additive or competing effects of multiple drugs. The most serious of these involve medications that increase a patient’s risk of serotonin syndrome or neuroleptic malignant syndrome (NMS); both are medical emergencies that require immediate hospitalization.

Although any medication with serotonergic activity can induce serotonin syndrome, combinations of serotonergic drugs in particular are associated with increased risk.¹⁰ Serotonin syndrome is characterized by hyperthermia, altered muscle tone, altered mental status, and autonomic instability; rhabdomyolysis and disseminated intravascular coagulation are potential lethal complications.¹⁰ A high index of suspicion can help clinicians rapidly detect serotonin syndrome, discontinue offending agents, and initiate supportive treatments.

NMS is a life-threatening complication of antipsychotics characterized by fever, delirium, muscle rigidity, autonomic instability, and abnormal laboratory findings that include elevated white blood count and increased creatinine kinase from muscle injury. In early stages, NMS may be mistaken for extrapyramidal symptoms. Although NMS can occur with any antipsychotic as monotherapy, additive antidopaminergic effects increase the risk. Patients with a compromised CNS as a result of mental retardation, traumatic brain injury, or metabolic abnormalities also are at increased risk of developing NMS.¹¹

Other pharmacodynamic interactions involve medications that may have additive effects on prolonging QTc intervals. For example, TCAs are pro-arrhythmic and have quinidine-like effects, which can cause cardiac conduction abnormalities and prolonged PR and QTc intervals.¹² Employ routine ECG monitoring when prescribing multiple medications known to cause QTc prolongation, such as TCAs (Table 3).^13,14 The Arizona Center for Education and Research on Therapeutics (www.azcert.org) provides a searchable list of QT-prolonging drugs (see Related Resources).

Medications also can interact with food, disease states, and herbal supplements. Alcohol interacts with many CNS-active medications, including many psychotropics. Patients taking benzodiazepines may experience oversedation and respiratory depression from alcohol’s additive sedating effects.⁵ Advise patients to limit their alcohol intake while taking CNS-depressing psychotropics such as benzodiazepines, antipsychotics, and some antidepressants. Monoamine oxidase inhibitors (MAOIs) and tyramine-containing food—such as cheese, beer, preserved meat, and soy sauce—can lead to a dangerous hypertensive crisis that requires immediate medical intervention to prevent life-threatening complications.⁵ Hypertensive crisis may be more significant in patients who have pre-existing hypertension. Finally, herbal supplements also can interact with medications. Patients who take St. John’s wort for depressive symptoms might not realize that it can reduce the efficacy of other drugs or increase their risk of serotonin syndrome.⁹

Table 2

Cytochrome P450 substrates, inhibitors, and inducers

Table 3

Psychotropics associated with QT prolongation

Black-box warnings

“Black-box” warnings issued by the FDA are included in the package insert to highlight a medication’s risks of dangerous and potentially lethal adverse effects. Table 4 highlights current black-box warnings for various psychotropics.^5,14-16

Antidepressants and suicide. All medications with antidepressant indications carry a black-box warning for risk of suicidal ideation and behavior in children, adolescents, and young adults during the early months of medication therapy. This includes not only SSRIs and serotonin-norepinephrine reuptake inhibitors, but also anticonvulsants and atypical antipsychotics indicated for treating mood disorders. Monitor young patients carefully and advise family members to alert clinicians of any signs of suicidality or unusual behavior.

Lamotrigine and aseptic meningitis. Aseptic meningitis—inflammation of the meninges that is not caused by bacteria—is a rare but serious adverse effect of lamotrigine. Symptoms include headache, fever, stiff neck, nausea and vomiting, delirium, rash, and sensitivity to light.⁵ Forty cases of aseptic meningitis in children and adults were reported over 15 years, representing <.01% of all lamotrigine prescriptions.⁵ Most of these patients required hospitalization, but symptoms resolved after lamotrigine was discontinued. Prompt identification and management of aseptic meningitis are necessary to prevent permanent brain damage and death. Other complications of aseptic meningitis include long-term neurologic sequelae such as cognitive impairment, seizure disorders, and behavioral disturbances.

Table 4

Which psychotropics carry ‘black-box’ warnings?

Other complications

Hematologic effects. All classes of psychotropics carry a risk (1 to 2 cases per year per 100,00 patients) of serious hematologic complications, including neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura, and anemia.¹⁷ Agranulocytosis has been associated most commonly with clozapine, carbamazepine, and typical antipsychotics.¹⁷ SSRIs, which are widely prescribed, are associated with increased risk of bruising and bleeding. Patients with bleeding or platelet disorders are at an increased risk for these complications.¹⁷

Seizures. Several classes of psychotropics are associated with an increased risk of seizures. Among antipsychotics, clozapine and chlorpromazine are the most seizurogenic.¹⁸ Among antidepressants, bupropion and clomipramine are most likely to lower seizure thresholds.¹⁸ Psychotropics’ seizure-inducing effects are dose-related. Vulnerability to seizures while taking psychotropics is related to having a history of epilepsy or brain injury.¹⁸ Seizures also can occur when benzodiazepines or anticonvulsants are withdrawn too quickly.

Heat stroke. Although a rare occurrence, psychotropics with anticholinergic side effects can contribute to heat stroke. Older patients are particularly vulnerable to the risk of body temperature dysregulation.¹⁹

Ketoacidosis and hyperosmolar coma. Medication-related deaths have occurred as a result of ketoacidosis and hyperosmolar coma associated with atypical antipsychotics. These hyperglycemia-related fatalities are most likely with clozapine and olanzapine.²⁰

Hip fractures and falls. Geriatric patients are vulnerable to falls and resultant hip fractures related to use of TCAs, SSRIs, benzodiazepines, and antipsychotics. This is not a trivial matter; hip fractures increase the mortality rate by 12% to 20% in the year after the injury.²¹ The risk of falls is related to sedation, orthostatic hypotension, arrhythmias, and confusion associated with psychotropics.^21,22

Akathisia and suicide. Unrecognized or undertreated akathisia is most commonly associated with antipsychotics, but also can occur with SSRIs. Although akathisia is commonly thought of as a motor syndrome of restlessness, patients may find the less-recognized psychic symptoms of increased inner turmoil and hallucinations just as distressing. This complex of symptoms is associated with an increased risk of suicide.²³ If discontinuing the offending agent is not feasible, akathisia can be treated with beta blockers, benzodiazepines, or anticholinergics.²⁴

Hepatotoxicity. Hepatotoxicity from psychotropics occurs in only a small percentage of patients, and can range from transient elevations in liver enzymes to fulminant liver failure. Adverse hepatic effects may be a manifestation of a hypersensitivity reaction accompanied by rash and eosinophilia.²⁵ MAOIs and TCAs can cause cholestatic liver injury, whereas nefazodone has been associated with fulminant liver failure. Other psychotropics—including SSRIs, antipsychotics, benzodiazepines, and older antiepileptics—can cause negative hepatic effects but rarely are associated with acute liver failure.^25,26 Although few medications can cause complete liver failure on their own, hepatotoxicity from medications may precipitate severe, potentially fatal outcomes in patients with underlying liver diseases such as hepatitis and cirrhosis. Additive hepatotoxicity from multiple medications also can be problematic. Although psychotropic-induced hepatotoxicity is rare, assess psychotropic doses in patients with liver dysfunction, because drug clearance may be altered, which increases the risk for other serious adverse events.²⁵

Suicide assessment is key

Ongoing monitoring for current or developing suicidal ideation is an important strategy to prevent medication-related mortality in patients vulnerable to self-harm. Initial assessments and follow-up appointments should include a detailed inquiry about suicidal ideations, plans, and behaviors. Patients taking medications that carry black-box warnings for suicide risk should be seen frequently during the first few months of treatment. Patients receiving medications that are lethal in overdose (eg, lithium and TCAs) should be carefully screened for suicide risk. Prescribe medications in limited quantities or arrange for a family member to monitor the patient if necessary. Patients with a history of suicide attempts and current suicide plans may require close observation and initiating medications while hospitalized.

Other prevention strategies

Prescribing psychotropics in a manner that promotes mental well being while minimizing negative outcomes can be challenging. By developing a personal formulary of drugs commonly encountered and prescribed in their practice, psychiatrists can increase their awareness of serious safety concerns, potential DDIs, and appropriate use based on available literature.^7,27

Medication histories and drug reconciliation—comparing a patient’s medication orders to all of the medications the patient has been taking—can help clinicians avoid making inappropriate dose adjustments, duplicating therapy, or prescribing medications patients previously have failed or did not tolerate. Establishing a collaborative practice environment with physicians, pharmacists, nurses, and social workers can minimize medication errors and risk of adverse outcomes by increasing communication regarding the patient’s treatment.⁷

Computerized drug databases and other electronic resources and consultation with pharmacists can help prescribers identify, avoid, and manage clinically significant DDIs.²⁷ Medications could interact with other drugs as long as their effects persist in the body, which could be days to months after the drug is discontinued. Future research may lead to tools to identify patient pharmacogenetic profiles.

Recognizing psychotropic DDIs and adverse effects remains a challenge because of the complexity of the affected organ, the brain. Clinicians should be vigilant to changes in a patient’s presentation because they may be a manifestation of a medication side effect.⁷ Appropriate therapeutic drug monitoring should occur on a routine, scheduled basis. Closer monitoring may be necessary with dose changes, potential DDIs, signs and symptoms of toxicity/efficacy failure, and renal or hepatic function changes.

Lastly, patients’ education and involvement in their health care may increase their awareness, responsibility, and medication adherence. For challenging patients, family involvement and “eyes on” medication administration can increase adherence and prevent psychotropic misuse.

Related Resources

• Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval and/or induce Torsades de Pointes ventricular arrhythmia. www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
• Cates ME, Sims PJ. Therapeutic drug management of lithium. Am J Pharm Educ. 2005;69(5):88.
• Wren P, Frizzell LA, Keltner NL, et al. Three potentially fatal adverse effects of psychotropic medications. Perspect Psychiatr Care. 2003;39(2):75-81.
• Bishop JR, Bishop DL. How to prevent serotonin syndrome from drug-drug interactions. Current Psychiatry. 2011;10(3):81-83.

Drug Brand Names

• Amantadine • Symmetrel
• Amiodarone • Cordarone, Pacerone
• Amitriptyline • Elavil
• Amphetamine/dextroamphetamine • Adderall, others
• Aprepitant • Emend
• Aripiprazole • Abilify
• Asenapine • Saphris
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol, others
• Chloral hydrate • Somnote
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Diltiazem • Cardia, others
• Diphenhydramine • Benadryl, others
• Doxepin • Sinequan, Silenor
• Duloxetine • Cymbalta
• Erythromycin • Ery-Tab, others
• Fluconazole • Diflucan
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Galantamine • Razadyne
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Imatinib • Gleevec
• Imipramine • Tofranil
• Isoniazid • Nydrazid, others
• Ketoconazole • Nizoral, others
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Methadone • Dolophine, Methadose
• Methylphenidate/ dexmethylphenidate • Ritalin, others
• Mirtazapine • Remeron
• Nafcillin • Nafcil, others
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxcarbazepine • Trileptal
• Paliperidone • Invega
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenobarbital • Luminal, others
• Phenytoin • Dilantin
• Protriptyline • Vivactil
• Quetiapine • Seroquel
• Rifampin • Rifadin, others
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trimethoprim/Sulfamethoxazole • Bactrim, Septra
• Trimipramine • Surmontil
• Valproic acid • Depakote, others
• Venlafaxine • Effexor
• Verapamil • Calan, others
• Ziprasidone • Geodon

Disclosure

Drs. Yu and Bostwick report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca, Pfizer Inc, and Sunovion Pharmaceuticals.

Medication errors due to system-, provider-, or patient-related factors contribute significantly to increased costs, adverse drug events (ADEs), and morbidity and mortality.¹ One study found >60% of ADEs that led to hospitalization could have been prevented by strategies such as adequate monitoring or appropriate prescribing.² Psychiatrists have an opportunity to reduce rates of ADEs; however, the possibility of disease symptoms overlapping with these adverse events is 1 of many obstacles prescribing clinicians face.¹ Prescribers also must contend with adverse effects of polypharmacy, which are common among psychiatric patients. Patient-related factors of concern include:

• seeing multiple prescribers
• medication nonadherence
• failure to communicate use of herbal or over-the-counter products
• lack of insight
• comorbid medical and psychiatric diagnoses, such as dementia.¹

This article highlights potential ADEs and major medication safety concerns that may contribute to morbidity and mortality among patients taking psychotropics. Although many factors are beyond the prescribing clinician’s control—such as medication dispensing and administration errors—psychiatrists can substantially reduce ADEs. We will cover potential adverse events associated with key medications or medication classes, drug interactions with potentially devastating consequences, and strategies to minimize risks of ADEs, including enhanced awareness and monitoring (Table 1).

Table 1

How to avoid ADEs with psychotropics

Prescription drug overdose

Each year, unintentional drug overdoses account for >20,000 deaths in the United States.³ Prescription medications, particularly opioid analgesics, have contributed to the doubling of overdose mortality rates in recent years. A recent study reported that nearly 50% of unintentional drug overdose deaths were associated with psychotropics and one-third of these deaths were associated with benzodiazepines, many of which were not prescribed to the individual.⁴

The risk of mortality from intentional drug overdose also must be assessed. Tricyclic antidepressants (TCAs) are a particularly lethal class of medications in suicide attempts and may result in arrhythmias, coma, seizures, respiratory failure, and death.⁵ Venlafaxine and mirtazapine are associated with greater risk of death and toxicity in overdose, respectively, than selective serotonin reuptake inhibitors (SSRIs).⁶ Lithium toxicity in overdose may lead to bradycardia, seizure, coma, hyperventilation, serotonin syndrome, respiratory failure, or death.⁵ The risk of death with lithium or benzodiazepine monotherapy is low when these agents are taken as prescribed. However, prescribers must exercise caution when these agents are used in combination. Interactions involving drugs with a narrow therapeutic index—such as lithium and TCAs—are more likely to be clinically significant because small increases in drug concentration can lead to serious adverse effects or death. See Related Resources for a review article on appropriate use and monitoring of lithium.

Drug-drug interactions

Many Americans take multiple prescription and nonprescription drugs, and psychiatric patients are more likely than other individuals to have more complex medication regimens.⁷ This can result in polypharmacy and drug-drug interactions (DDIs), which can lead to undesired medication effects and serious, potentially fatal ADEs.

Pharmacokinetic interactions typically affect drug concentrations and occur when 1 drug interferes with the absorption, distribution, metabolism, or excretion of another drug. Many common pharmacokinetic interactions involve the liver cytochrome P450 (CYP) system, which is responsible for metabolizing many medications.⁸ DDIs can occur when CYP enzymes are modified by inhibitors or inducers, which can decrease or increase drug clearance, respectively. Table 2 ^5,7,9 provides examples of common CYP450 substrates, inhibitors, and inducers. Polymorphisms in the pharmacogenetics of CYP450 also can affect overall drug clearance and the impact of DDIs.⁸

Pharmacodynamic interactions are caused by additive or competing effects of multiple drugs. The most serious of these involve medications that increase a patient’s risk of serotonin syndrome or neuroleptic malignant syndrome (NMS); both are medical emergencies that require immediate hospitalization.

Although any medication with serotonergic activity can induce serotonin syndrome, combinations of serotonergic drugs in particular are associated with increased risk.¹⁰ Serotonin syndrome is characterized by hyperthermia, altered muscle tone, altered mental status, and autonomic instability; rhabdomyolysis and disseminated intravascular coagulation are potential lethal complications.¹⁰ A high index of suspicion can help clinicians rapidly detect serotonin syndrome, discontinue offending agents, and initiate supportive treatments.

NMS is a life-threatening complication of antipsychotics characterized by fever, delirium, muscle rigidity, autonomic instability, and abnormal laboratory findings that include elevated white blood count and increased creatinine kinase from muscle injury. In early stages, NMS may be mistaken for extrapyramidal symptoms. Although NMS can occur with any antipsychotic as monotherapy, additive antidopaminergic effects increase the risk. Patients with a compromised CNS as a result of mental retardation, traumatic brain injury, or metabolic abnormalities also are at increased risk of developing NMS.¹¹

Other pharmacodynamic interactions involve medications that may have additive effects on prolonging QTc intervals. For example, TCAs are pro-arrhythmic and have quinidine-like effects, which can cause cardiac conduction abnormalities and prolonged PR and QTc intervals.¹² Employ routine ECG monitoring when prescribing multiple medications known to cause QTc prolongation, such as TCAs (Table 3).^13,14 The Arizona Center for Education and Research on Therapeutics (www.azcert.org) provides a searchable list of QT-prolonging drugs (see Related Resources).

Medications also can interact with food, disease states, and herbal supplements. Alcohol interacts with many CNS-active medications, including many psychotropics. Patients taking benzodiazepines may experience oversedation and respiratory depression from alcohol’s additive sedating effects.⁵ Advise patients to limit their alcohol intake while taking CNS-depressing psychotropics such as benzodiazepines, antipsychotics, and some antidepressants. Monoamine oxidase inhibitors (MAOIs) and tyramine-containing food—such as cheese, beer, preserved meat, and soy sauce—can lead to a dangerous hypertensive crisis that requires immediate medical intervention to prevent life-threatening complications.⁵ Hypertensive crisis may be more significant in patients who have pre-existing hypertension. Finally, herbal supplements also can interact with medications. Patients who take St. John’s wort for depressive symptoms might not realize that it can reduce the efficacy of other drugs or increase their risk of serotonin syndrome.⁹

Table 2

Cytochrome P450 substrates, inhibitors, and inducers

Table 3

Psychotropics associated with QT prolongation

Black-box warnings

“Black-box” warnings issued by the FDA are included in the package insert to highlight a medication’s risks of dangerous and potentially lethal adverse effects. Table 4 highlights current black-box warnings for various psychotropics.^5,14-16

Antidepressants and suicide. All medications with antidepressant indications carry a black-box warning for risk of suicidal ideation and behavior in children, adolescents, and young adults during the early months of medication therapy. This includes not only SSRIs and serotonin-norepinephrine reuptake inhibitors, but also anticonvulsants and atypical antipsychotics indicated for treating mood disorders. Monitor young patients carefully and advise family members to alert clinicians of any signs of suicidality or unusual behavior.

Lamotrigine and aseptic meningitis. Aseptic meningitis—inflammation of the meninges that is not caused by bacteria—is a rare but serious adverse effect of lamotrigine. Symptoms include headache, fever, stiff neck, nausea and vomiting, delirium, rash, and sensitivity to light.⁵ Forty cases of aseptic meningitis in children and adults were reported over 15 years, representing <.01% of all lamotrigine prescriptions.⁵ Most of these patients required hospitalization, but symptoms resolved after lamotrigine was discontinued. Prompt identification and management of aseptic meningitis are necessary to prevent permanent brain damage and death. Other complications of aseptic meningitis include long-term neurologic sequelae such as cognitive impairment, seizure disorders, and behavioral disturbances.

Table 4

Which psychotropics carry ‘black-box’ warnings?

Other complications

Hematologic effects. All classes of psychotropics carry a risk (1 to 2 cases per year per 100,00 patients) of serious hematologic complications, including neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura, and anemia.¹⁷ Agranulocytosis has been associated most commonly with clozapine, carbamazepine, and typical antipsychotics.¹⁷ SSRIs, which are widely prescribed, are associated with increased risk of bruising and bleeding. Patients with bleeding or platelet disorders are at an increased risk for these complications.¹⁷

Seizures. Several classes of psychotropics are associated with an increased risk of seizures. Among antipsychotics, clozapine and chlorpromazine are the most seizurogenic.¹⁸ Among antidepressants, bupropion and clomipramine are most likely to lower seizure thresholds.¹⁸ Psychotropics’ seizure-inducing effects are dose-related. Vulnerability to seizures while taking psychotropics is related to having a history of epilepsy or brain injury.¹⁸ Seizures also can occur when benzodiazepines or anticonvulsants are withdrawn too quickly.

Heat stroke. Although a rare occurrence, psychotropics with anticholinergic side effects can contribute to heat stroke. Older patients are particularly vulnerable to the risk of body temperature dysregulation.¹⁹

Ketoacidosis and hyperosmolar coma. Medication-related deaths have occurred as a result of ketoacidosis and hyperosmolar coma associated with atypical antipsychotics. These hyperglycemia-related fatalities are most likely with clozapine and olanzapine.²⁰

Hip fractures and falls. Geriatric patients are vulnerable to falls and resultant hip fractures related to use of TCAs, SSRIs, benzodiazepines, and antipsychotics. This is not a trivial matter; hip fractures increase the mortality rate by 12% to 20% in the year after the injury.²¹ The risk of falls is related to sedation, orthostatic hypotension, arrhythmias, and confusion associated with psychotropics.^21,22

Akathisia and suicide. Unrecognized or undertreated akathisia is most commonly associated with antipsychotics, but also can occur with SSRIs. Although akathisia is commonly thought of as a motor syndrome of restlessness, patients may find the less-recognized psychic symptoms of increased inner turmoil and hallucinations just as distressing. This complex of symptoms is associated with an increased risk of suicide.²³ If discontinuing the offending agent is not feasible, akathisia can be treated with beta blockers, benzodiazepines, or anticholinergics.²⁴

Hepatotoxicity. Hepatotoxicity from psychotropics occurs in only a small percentage of patients, and can range from transient elevations in liver enzymes to fulminant liver failure. Adverse hepatic effects may be a manifestation of a hypersensitivity reaction accompanied by rash and eosinophilia.²⁵ MAOIs and TCAs can cause cholestatic liver injury, whereas nefazodone has been associated with fulminant liver failure. Other psychotropics—including SSRIs, antipsychotics, benzodiazepines, and older antiepileptics—can cause negative hepatic effects but rarely are associated with acute liver failure.^25,26 Although few medications can cause complete liver failure on their own, hepatotoxicity from medications may precipitate severe, potentially fatal outcomes in patients with underlying liver diseases such as hepatitis and cirrhosis. Additive hepatotoxicity from multiple medications also can be problematic. Although psychotropic-induced hepatotoxicity is rare, assess psychotropic doses in patients with liver dysfunction, because drug clearance may be altered, which increases the risk for other serious adverse events.²⁵

Suicide assessment is key

Ongoing monitoring for current or developing suicidal ideation is an important strategy to prevent medication-related mortality in patients vulnerable to self-harm. Initial assessments and follow-up appointments should include a detailed inquiry about suicidal ideations, plans, and behaviors. Patients taking medications that carry black-box warnings for suicide risk should be seen frequently during the first few months of treatment. Patients receiving medications that are lethal in overdose (eg, lithium and TCAs) should be carefully screened for suicide risk. Prescribe medications in limited quantities or arrange for a family member to monitor the patient if necessary. Patients with a history of suicide attempts and current suicide plans may require close observation and initiating medications while hospitalized.

Other prevention strategies

Prescribing psychotropics in a manner that promotes mental well being while minimizing negative outcomes can be challenging. By developing a personal formulary of drugs commonly encountered and prescribed in their practice, psychiatrists can increase their awareness of serious safety concerns, potential DDIs, and appropriate use based on available literature.^7,27

Medication histories and drug reconciliation—comparing a patient’s medication orders to all of the medications the patient has been taking—can help clinicians avoid making inappropriate dose adjustments, duplicating therapy, or prescribing medications patients previously have failed or did not tolerate. Establishing a collaborative practice environment with physicians, pharmacists, nurses, and social workers can minimize medication errors and risk of adverse outcomes by increasing communication regarding the patient’s treatment.⁷

Computerized drug databases and other electronic resources and consultation with pharmacists can help prescribers identify, avoid, and manage clinically significant DDIs.²⁷ Medications could interact with other drugs as long as their effects persist in the body, which could be days to months after the drug is discontinued. Future research may lead to tools to identify patient pharmacogenetic profiles.

Recognizing psychotropic DDIs and adverse effects remains a challenge because of the complexity of the affected organ, the brain. Clinicians should be vigilant to changes in a patient’s presentation because they may be a manifestation of a medication side effect.⁷ Appropriate therapeutic drug monitoring should occur on a routine, scheduled basis. Closer monitoring may be necessary with dose changes, potential DDIs, signs and symptoms of toxicity/efficacy failure, and renal or hepatic function changes.

Lastly, patients’ education and involvement in their health care may increase their awareness, responsibility, and medication adherence. For challenging patients, family involvement and “eyes on” medication administration can increase adherence and prevent psychotropic misuse.

Related Resources

• Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval and/or induce Torsades de Pointes ventricular arrhythmia. www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
• Cates ME, Sims PJ. Therapeutic drug management of lithium. Am J Pharm Educ. 2005;69(5):88.
• Wren P, Frizzell LA, Keltner NL, et al. Three potentially fatal adverse effects of psychotropic medications. Perspect Psychiatr Care. 2003;39(2):75-81.
• Bishop JR, Bishop DL. How to prevent serotonin syndrome from drug-drug interactions. Current Psychiatry. 2011;10(3):81-83.

Drug Brand Names

• Amantadine • Symmetrel
• Amiodarone • Cordarone, Pacerone
• Amitriptyline • Elavil
• Amphetamine/dextroamphetamine • Adderall, others
• Aprepitant • Emend
• Aripiprazole • Abilify
• Asenapine • Saphris
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol, others
• Chloral hydrate • Somnote
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Diltiazem • Cardia, others
• Diphenhydramine • Benadryl, others
• Doxepin • Sinequan, Silenor
• Duloxetine • Cymbalta
• Erythromycin • Ery-Tab, others
• Fluconazole • Diflucan
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Galantamine • Razadyne
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Imatinib • Gleevec
• Imipramine • Tofranil
• Isoniazid • Nydrazid, others
• Ketoconazole • Nizoral, others
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Methadone • Dolophine, Methadose
• Methylphenidate/ dexmethylphenidate • Ritalin, others
• Mirtazapine • Remeron
• Nafcillin • Nafcil, others
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxcarbazepine • Trileptal
• Paliperidone • Invega
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenobarbital • Luminal, others
• Phenytoin • Dilantin
• Protriptyline • Vivactil
• Quetiapine • Seroquel
• Rifampin • Rifadin, others
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trimethoprim/Sulfamethoxazole • Bactrim, Septra
• Trimipramine • Surmontil
• Valproic acid • Depakote, others
• Venlafaxine • Effexor
• Verapamil • Calan, others
• Ziprasidone • Geodon

Disclosure

Drs. Yu and Bostwick report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca, Pfizer Inc, and Sunovion Pharmaceuticals.