Michael I. Casher, MD

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatrists who are accustomed to working with “med/surg” or psychiatric nurses may be less familiar with how to collaborate with more specialized psychiatric-mental health nurse practitioners (PMHNPs). These clinicians play an important role in delivering mental health services, which is likely to continue because of the physician shortage in the United States¹ and increasing mental health care needs from passage of the Affordable Health Care Act and the Mental Health Parity Act.² These specialty trained, master’s level nurses work with psychiatrists in outpatient clinics, hospital consultation and liaison services, psychiatric emergency services, inpatient units, and geropsychiatric consultation.^3-5 PMHNPs can fill gaps of coverage in underserved areas, supplement and complement busy and overburdened psychiatrists, and add an important dimension of holistic care.

This article reviews issues related to a successful psychiatrist-PMHNP collaboration, including:

• PMHNP’s training and scope of practice
  
• their skill and competency development in inpatient and outpatient settings
  
• the principles and dynamics of collaboration, hindrances to cooperation, and keys to relationship-building for PMHNPs and psychiatrists.
  

Rigorous requirements

PMHNPs enroll in an accredited graduate nursing program that takes 16 to 24 months to complete and builds on the competencies of their undergraduate nursing education and clinical experience. All programs meet standards set by national nursing accrediting agencies. The typical graduate-level curriculum for a PMHNP includes core bio-behavioral theory, research courses, advanced physiology and pathophysiology, advanced physical and psychiatric health assessment, pharmacologic and nonpharmacologic interventions, and managing health care delivery systems. For graduation and certification, PMHNPs must complete 500 supervised clinical hours focused on psychiatric and mental health care.

• comprehensive psychiatric evaluation
  
• formulation of a differential diagnosis
  
• ordering and interpreting diagnostic tests
  
• prescribing pharmacologic agents
  
• conducting individual, couple, group, or family psychotherapy using evidence-based approaches.
  

PMHNPs also are responsible for recognizing the limits of their knowledge and experience, planning for situations beyond their expertise, and providing appropriate referral to other health care providers when indicated.⁸

Successful collaborative practice requires a clear definition and understanding of roles.⁹ This is particularly important for collaborating psychiatrists and PMHNPs because there has been confusion among physicians and the general public related to the nurse practitioner’s role. Psychiatrists who work with PMHNPs need to be familiar with state regulations that govern levels of physician supervision and prescriptive authority for nurse practitioners. Eleven states and the District of Columbia allow nurse practitioners to prescribe independently, including controlled substances. Most states require physician collaboration for prescribing medications, but the language can be ambiguous, with restrictions on certain formularies or drug schedules—eg, Michigan nurse practitioners may prescribe schedule II through V controlled substances, but schedule II medications are limited to nurse practitioners who work in hospitals, surgical outpatient settings, or hospices.¹⁰

Competencies and development

New PMHNPs see patients and prescribe medication, but their work needs close supervision. Postgraduate clinical experience combined with supervision gradually allows the PMHNP greater independence. A PMHNP who provides care in a busy outpatient clinic, inpatient unit, or psychiatric emergency department is likely to master the treatment philosophy and ancillary competencies related to that particular clinical site—including favored pharmacologic approaches, electronic documentation and ordering functions, and admission and discharge facilitation—at a level exceeding that of psychiatric residents, who rotate on and off a service as part of their training.

It’s helpful for new PMHNPs to have a time frame for their development over several years. The Table¹¹ outlines general graded competency areas PMHNPs may focus on in their development. See this article at CurrentPsychiatry.com for Tables that provide examples of detailed competencies for third-year PMHNPs in inpatient and outpatient settings.

Table

PMHNP development: General graded competency areas

Competencies for third-year PMHNPs in an outpatient clinic

Competencies for third-year PMHNPs on an inpatient psychiatric unit

Principles of practice

Studies have demonstrated the importance of understanding how to effectively implement collaborative care across medical disciplines.¹² See the Box¹² for a discussion of 3 key determinants for successful clinical collaborations.

Box

Enhancing collaboration

Psychiatrists who work with PMHNPs develop trust based on observing each PMHNP’s work, including their relationship with patients, ability to conceptualize a case and develop a treatment plan, and the skill with which they function within a team. The psychiatrist’s comfort level also is related to his or her awareness of the comprehensiveness of the PMHNP’s training and the competencies gained from clinical experience. Respect for the PMHNP’s educational and professional background is the foundation for what is often—at least in the collaborative relationship’s initial stages—a combined cooperative and supervisory relationship with the PMHNP. As such, the PMHNP gradually will absorb certain “intangibles” to supplement the training and work experiences that preceded his or her position. This may include assimilating the psychiatrist’s or clinic’s philosophy and treatment practice, including expertise in dealing with specialized psychiatric populations (eg, developmental disabilities, acute psychosis, or treatment-resistant depression).

The patient’s comfort level

Collaborating PMHNPs and psychiatrists need to be prepared for a patient who expresses disappointment with being treated by a PMHNP or a preference to see “a doctor.” Psychiatrists who have not worked through their own ambivalence about the collaboration or who lack confidence in the PMHNP’s abilities may find themselves consciously or unconsciously aligning with the patient’s stance. They may neglect to explore the basis and meaning of the patient’s preference, which may be related to the patient’s lack of knowledge about the PMHNP’s role and training. The PMHNP who encounters such a patient has a more challenging task—namely, how to calmly address the patient’s concern while the patient is challenging the PMHNP’s competence. Both the PMHNP and psychiatrist need to be alert to the possibility of “splitting” in the treatment of axis II-disordered patients.

Barriers to collaboration

From the PMHNP perspective, barriers to a collaborative relationship include referring to PMHNPs by a less preferred term or title, instead of a nurse practitioner or APN, which can hinder the relationship. Although physician assistants and NPs have been grouped together under the term “mid-level providers,” the American Academy of Nurse Practitioners notes that this term suggests a lower level of care or service is being provided.¹⁸ “Physician extender” is another term that fails to recognize the PMHNP’s separate and unique role and the PMHNP’s view of their role as complementary to medicine, rather than an extension of a physician’s practice.

Territorial issues can impede collaborative relationships. Psychiatrists who resist collaborating will be less effective than those who welcome a PMHNP and readily delegate specific tasks and portions of the workload, whereas psychiatrists who value the help will be more likely to build a collaborative partnership, leading to better patient care.

Autonomy is a critical determinant of professional satisfaction for PMHNPs. A PMHNP’s autonomy can be impeded by organizational constraints and physician perceptions.¹⁹ PMHNPs require autonomy to self-direct patient diagnosis and treatment within the scope of their practice, and many find this relative independence essential to delivering high quality patient care. Lack of autonomy can lead to breaks in workflow in the outpatient setting and increased length of stay for hospitalized patients. In addition, an autonomously functioning, experienced PMHNP can increase efficiency in hospital settings where psychiatrists can be in short supply, preoccupied with administrative matters, or require help on weekends.

Related Resources

• American Psychiatric Nurses Association. www.apna.org.
  
• International Society of Psychiatric-Mental Health Nurses. www.ispn-psych.org.
  
• American Nurses Association. www.nursingworld.org.
  

Dr. Casher is a speaker for Sunovion Pharmaceuticals and receives royalties from Cambridge University Press.

Ms. Kuebler, Ms. Bastida, and Ms. Chipps report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatrists who are accustomed to working with “med/surg” or psychiatric nurses may be less familiar with how to collaborate with more specialized psychiatric-mental health nurse practitioners (PMHNPs). These clinicians play an important role in delivering mental health services, which is likely to continue because of the physician shortage in the United States¹ and increasing mental health care needs from passage of the Affordable Health Care Act and the Mental Health Parity Act.² These specialty trained, master’s level nurses work with psychiatrists in outpatient clinics, hospital consultation and liaison services, psychiatric emergency services, inpatient units, and geropsychiatric consultation.^3-5 PMHNPs can fill gaps of coverage in underserved areas, supplement and complement busy and overburdened psychiatrists, and add an important dimension of holistic care.

This article reviews issues related to a successful psychiatrist-PMHNP collaboration, including:

• PMHNP’s training and scope of practice
  
• their skill and competency development in inpatient and outpatient settings
  
• the principles and dynamics of collaboration, hindrances to cooperation, and keys to relationship-building for PMHNPs and psychiatrists.
  

Rigorous requirements

PMHNPs enroll in an accredited graduate nursing program that takes 16 to 24 months to complete and builds on the competencies of their undergraduate nursing education and clinical experience. All programs meet standards set by national nursing accrediting agencies. The typical graduate-level curriculum for a PMHNP includes core bio-behavioral theory, research courses, advanced physiology and pathophysiology, advanced physical and psychiatric health assessment, pharmacologic and nonpharmacologic interventions, and managing health care delivery systems. For graduation and certification, PMHNPs must complete 500 supervised clinical hours focused on psychiatric and mental health care.

• comprehensive psychiatric evaluation
  
• formulation of a differential diagnosis
  
• ordering and interpreting diagnostic tests
  
• prescribing pharmacologic agents
  
• conducting individual, couple, group, or family psychotherapy using evidence-based approaches.
  

PMHNPs also are responsible for recognizing the limits of their knowledge and experience, planning for situations beyond their expertise, and providing appropriate referral to other health care providers when indicated.⁸

Successful collaborative practice requires a clear definition and understanding of roles.⁹ This is particularly important for collaborating psychiatrists and PMHNPs because there has been confusion among physicians and the general public related to the nurse practitioner’s role. Psychiatrists who work with PMHNPs need to be familiar with state regulations that govern levels of physician supervision and prescriptive authority for nurse practitioners. Eleven states and the District of Columbia allow nurse practitioners to prescribe independently, including controlled substances. Most states require physician collaboration for prescribing medications, but the language can be ambiguous, with restrictions on certain formularies or drug schedules—eg, Michigan nurse practitioners may prescribe schedule II through V controlled substances, but schedule II medications are limited to nurse practitioners who work in hospitals, surgical outpatient settings, or hospices.¹⁰

Competencies and development

New PMHNPs see patients and prescribe medication, but their work needs close supervision. Postgraduate clinical experience combined with supervision gradually allows the PMHNP greater independence. A PMHNP who provides care in a busy outpatient clinic, inpatient unit, or psychiatric emergency department is likely to master the treatment philosophy and ancillary competencies related to that particular clinical site—including favored pharmacologic approaches, electronic documentation and ordering functions, and admission and discharge facilitation—at a level exceeding that of psychiatric residents, who rotate on and off a service as part of their training.

It’s helpful for new PMHNPs to have a time frame for their development over several years. The Table¹¹ outlines general graded competency areas PMHNPs may focus on in their development. See this article at CurrentPsychiatry.com for Tables that provide examples of detailed competencies for third-year PMHNPs in inpatient and outpatient settings.

Table

PMHNP development: General graded competency areas

Competencies for third-year PMHNPs in an outpatient clinic

Competencies for third-year PMHNPs on an inpatient psychiatric unit

Principles of practice

Studies have demonstrated the importance of understanding how to effectively implement collaborative care across medical disciplines.¹² See the Box¹² for a discussion of 3 key determinants for successful clinical collaborations.

Box

Enhancing collaboration

Psychiatrists who work with PMHNPs develop trust based on observing each PMHNP’s work, including their relationship with patients, ability to conceptualize a case and develop a treatment plan, and the skill with which they function within a team. The psychiatrist’s comfort level also is related to his or her awareness of the comprehensiveness of the PMHNP’s training and the competencies gained from clinical experience. Respect for the PMHNP’s educational and professional background is the foundation for what is often—at least in the collaborative relationship’s initial stages—a combined cooperative and supervisory relationship with the PMHNP. As such, the PMHNP gradually will absorb certain “intangibles” to supplement the training and work experiences that preceded his or her position. This may include assimilating the psychiatrist’s or clinic’s philosophy and treatment practice, including expertise in dealing with specialized psychiatric populations (eg, developmental disabilities, acute psychosis, or treatment-resistant depression).

The patient’s comfort level

Collaborating PMHNPs and psychiatrists need to be prepared for a patient who expresses disappointment with being treated by a PMHNP or a preference to see “a doctor.” Psychiatrists who have not worked through their own ambivalence about the collaboration or who lack confidence in the PMHNP’s abilities may find themselves consciously or unconsciously aligning with the patient’s stance. They may neglect to explore the basis and meaning of the patient’s preference, which may be related to the patient’s lack of knowledge about the PMHNP’s role and training. The PMHNP who encounters such a patient has a more challenging task—namely, how to calmly address the patient’s concern while the patient is challenging the PMHNP’s competence. Both the PMHNP and psychiatrist need to be alert to the possibility of “splitting” in the treatment of axis II-disordered patients.

Barriers to collaboration

From the PMHNP perspective, barriers to a collaborative relationship include referring to PMHNPs by a less preferred term or title, instead of a nurse practitioner or APN, which can hinder the relationship. Although physician assistants and NPs have been grouped together under the term “mid-level providers,” the American Academy of Nurse Practitioners notes that this term suggests a lower level of care or service is being provided.¹⁸ “Physician extender” is another term that fails to recognize the PMHNP’s separate and unique role and the PMHNP’s view of their role as complementary to medicine, rather than an extension of a physician’s practice.

Territorial issues can impede collaborative relationships. Psychiatrists who resist collaborating will be less effective than those who welcome a PMHNP and readily delegate specific tasks and portions of the workload, whereas psychiatrists who value the help will be more likely to build a collaborative partnership, leading to better patient care.

Autonomy is a critical determinant of professional satisfaction for PMHNPs. A PMHNP’s autonomy can be impeded by organizational constraints and physician perceptions.¹⁹ PMHNPs require autonomy to self-direct patient diagnosis and treatment within the scope of their practice, and many find this relative independence essential to delivering high quality patient care. Lack of autonomy can lead to breaks in workflow in the outpatient setting and increased length of stay for hospitalized patients. In addition, an autonomously functioning, experienced PMHNP can increase efficiency in hospital settings where psychiatrists can be in short supply, preoccupied with administrative matters, or require help on weekends.

Related Resources

• American Psychiatric Nurses Association. www.apna.org.
  
• International Society of Psychiatric-Mental Health Nurses. www.ispn-psych.org.
  
• American Nurses Association. www.nursingworld.org.
  

Dr. Casher is a speaker for Sunovion Pharmaceuticals and receives royalties from Cambridge University Press.

Ms. Kuebler, Ms. Bastida, and Ms. Chipps report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatrists who are accustomed to working with “med/surg” or psychiatric nurses may be less familiar with how to collaborate with more specialized psychiatric-mental health nurse practitioners (PMHNPs). These clinicians play an important role in delivering mental health services, which is likely to continue because of the physician shortage in the United States¹ and increasing mental health care needs from passage of the Affordable Health Care Act and the Mental Health Parity Act.² These specialty trained, master’s level nurses work with psychiatrists in outpatient clinics, hospital consultation and liaison services, psychiatric emergency services, inpatient units, and geropsychiatric consultation.^3-5 PMHNPs can fill gaps of coverage in underserved areas, supplement and complement busy and overburdened psychiatrists, and add an important dimension of holistic care.

This article reviews issues related to a successful psychiatrist-PMHNP collaboration, including:

• PMHNP’s training and scope of practice
  
• their skill and competency development in inpatient and outpatient settings
  
• the principles and dynamics of collaboration, hindrances to cooperation, and keys to relationship-building for PMHNPs and psychiatrists.
  

Rigorous requirements

PMHNPs enroll in an accredited graduate nursing program that takes 16 to 24 months to complete and builds on the competencies of their undergraduate nursing education and clinical experience. All programs meet standards set by national nursing accrediting agencies. The typical graduate-level curriculum for a PMHNP includes core bio-behavioral theory, research courses, advanced physiology and pathophysiology, advanced physical and psychiatric health assessment, pharmacologic and nonpharmacologic interventions, and managing health care delivery systems. For graduation and certification, PMHNPs must complete 500 supervised clinical hours focused on psychiatric and mental health care.

• comprehensive psychiatric evaluation
  
• formulation of a differential diagnosis
  
• ordering and interpreting diagnostic tests
  
• prescribing pharmacologic agents
  
• conducting individual, couple, group, or family psychotherapy using evidence-based approaches.
  

PMHNPs also are responsible for recognizing the limits of their knowledge and experience, planning for situations beyond their expertise, and providing appropriate referral to other health care providers when indicated.⁸

Successful collaborative practice requires a clear definition and understanding of roles.⁹ This is particularly important for collaborating psychiatrists and PMHNPs because there has been confusion among physicians and the general public related to the nurse practitioner’s role. Psychiatrists who work with PMHNPs need to be familiar with state regulations that govern levels of physician supervision and prescriptive authority for nurse practitioners. Eleven states and the District of Columbia allow nurse practitioners to prescribe independently, including controlled substances. Most states require physician collaboration for prescribing medications, but the language can be ambiguous, with restrictions on certain formularies or drug schedules—eg, Michigan nurse practitioners may prescribe schedule II through V controlled substances, but schedule II medications are limited to nurse practitioners who work in hospitals, surgical outpatient settings, or hospices.¹⁰

Competencies and development

New PMHNPs see patients and prescribe medication, but their work needs close supervision. Postgraduate clinical experience combined with supervision gradually allows the PMHNP greater independence. A PMHNP who provides care in a busy outpatient clinic, inpatient unit, or psychiatric emergency department is likely to master the treatment philosophy and ancillary competencies related to that particular clinical site—including favored pharmacologic approaches, electronic documentation and ordering functions, and admission and discharge facilitation—at a level exceeding that of psychiatric residents, who rotate on and off a service as part of their training.

It’s helpful for new PMHNPs to have a time frame for their development over several years. The Table¹¹ outlines general graded competency areas PMHNPs may focus on in their development. See this article at CurrentPsychiatry.com for Tables that provide examples of detailed competencies for third-year PMHNPs in inpatient and outpatient settings.

Table

PMHNP development: General graded competency areas

Competencies for third-year PMHNPs in an outpatient clinic

Competencies for third-year PMHNPs on an inpatient psychiatric unit

Principles of practice

Studies have demonstrated the importance of understanding how to effectively implement collaborative care across medical disciplines.¹² See the Box¹² for a discussion of 3 key determinants for successful clinical collaborations.

Box

Enhancing collaboration

Psychiatrists who work with PMHNPs develop trust based on observing each PMHNP’s work, including their relationship with patients, ability to conceptualize a case and develop a treatment plan, and the skill with which they function within a team. The psychiatrist’s comfort level also is related to his or her awareness of the comprehensiveness of the PMHNP’s training and the competencies gained from clinical experience. Respect for the PMHNP’s educational and professional background is the foundation for what is often—at least in the collaborative relationship’s initial stages—a combined cooperative and supervisory relationship with the PMHNP. As such, the PMHNP gradually will absorb certain “intangibles” to supplement the training and work experiences that preceded his or her position. This may include assimilating the psychiatrist’s or clinic’s philosophy and treatment practice, including expertise in dealing with specialized psychiatric populations (eg, developmental disabilities, acute psychosis, or treatment-resistant depression).

The patient’s comfort level

Collaborating PMHNPs and psychiatrists need to be prepared for a patient who expresses disappointment with being treated by a PMHNP or a preference to see “a doctor.” Psychiatrists who have not worked through their own ambivalence about the collaboration or who lack confidence in the PMHNP’s abilities may find themselves consciously or unconsciously aligning with the patient’s stance. They may neglect to explore the basis and meaning of the patient’s preference, which may be related to the patient’s lack of knowledge about the PMHNP’s role and training. The PMHNP who encounters such a patient has a more challenging task—namely, how to calmly address the patient’s concern while the patient is challenging the PMHNP’s competence. Both the PMHNP and psychiatrist need to be alert to the possibility of “splitting” in the treatment of axis II-disordered patients.

Barriers to collaboration

From the PMHNP perspective, barriers to a collaborative relationship include referring to PMHNPs by a less preferred term or title, instead of a nurse practitioner or APN, which can hinder the relationship. Although physician assistants and NPs have been grouped together under the term “mid-level providers,” the American Academy of Nurse Practitioners notes that this term suggests a lower level of care or service is being provided.¹⁸ “Physician extender” is another term that fails to recognize the PMHNP’s separate and unique role and the PMHNP’s view of their role as complementary to medicine, rather than an extension of a physician’s practice.

Territorial issues can impede collaborative relationships. Psychiatrists who resist collaborating will be less effective than those who welcome a PMHNP and readily delegate specific tasks and portions of the workload, whereas psychiatrists who value the help will be more likely to build a collaborative partnership, leading to better patient care.

Autonomy is a critical determinant of professional satisfaction for PMHNPs. A PMHNP’s autonomy can be impeded by organizational constraints and physician perceptions.¹⁹ PMHNPs require autonomy to self-direct patient diagnosis and treatment within the scope of their practice, and many find this relative independence essential to delivering high quality patient care. Lack of autonomy can lead to breaks in workflow in the outpatient setting and increased length of stay for hospitalized patients. In addition, an autonomously functioning, experienced PMHNP can increase efficiency in hospital settings where psychiatrists can be in short supply, preoccupied with administrative matters, or require help on weekends.

Related Resources

• American Psychiatric Nurses Association. www.apna.org.
  
• International Society of Psychiatric-Mental Health Nurses. www.ispn-psych.org.
  
• American Nurses Association. www.nursingworld.org.
  

Dr. Casher is a speaker for Sunovion Pharmaceuticals and receives royalties from Cambridge University Press.

Ms. Kuebler, Ms. Bastida, and Ms. Chipps report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

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.

Although benzodiazepines and stimulants have well-documented efficacy for numerous psychiatric disorders, psychiatrists hesitate to prescribe these medications to patients with substance use disorders (SUDs)—even to those with a comorbid condition that likely would respond to a benzodiazepine or stimulant—because of risk of abuse or dependence. Conventional practice typically has focused on treating active substance use first rather than using simultaneous treatments. Prejudice, fear, and misinformation can influence this decision.

We believe these cases lie on a continuum. At one extreme, ignoring a past or present SUD may lead a remitted patient toward relapse, or further delay recovery for an active user. At the other end, psychiatrists who overreact to a remote history of substance use may deprive patients of legitimate pharmacologic symptom relief. Most cases lie somewhere in the middle.

A literature review does not support the assertion that the use of these medications leads to future substance use or worsens active use, especially for stimulants. In fact, stepwise—as opposed to concurrent—treatment for both conditions actually may delay recovery and increase patients’ risk for morbidity.

We outline issues involved in these complex clinical situations, point out controversies, review relevant research data, and offer guidelines for treatment.

CASE 1 Panic disorder in sobriety

Since he was a teen, Mr. A, age 51, drank heavily, which cost him jobs and relationships. After being convicted for driving under the influence, he was court-ordered to attend a rehabilitation facility, where, as he describes it, he “finally turned [his] life around.” He followed up residential treatment with regular attendance at Alcoholics Anonymous meetings.

After 1 year of sobriety, Mr. A develops increasingly frequent episodes of intense anxiety with sweating, nausea, chest pain, and hyperventilation and is diagnosed with panic disorder. His internist prescribes alprazolam, 0.5 mg 3 times a day, which provides some symptom relief, and refers him for follow-up psychiatric care. At his first visit, Mr. A confides to his psychiatrist that he is taking much more than the prescribed dosage of alprazolam, even when he is not experiencing anxiety, and is contemplating “buying it on the street” if his dosage is not raised to “at least 3 mg 3 times a day.”

CASE 2 Anxiety in controlled psychosis

Ms. B, age 40, had her first psychotic break at age 18 and was diagnosed with schizophrenia. Since then, she has had multiple psychiatric hospitalizations, usually presenting with auditory hallucinations and a recurring delusion that the person who calls herself Ms. B’s mother is really an actress “playing” her mother. At times this delusion has led Ms. B to attack her “imposter” mother. Over several years Ms. B began to drink heavily, but recently achieved a few months of sobriety by attending dual-diagnosis groups at her local community mental health center and individual psychotherapy sessions with her case manager. Fortunately, Ms. B’s psychosis has been stabilized with risperidone long-acting injection, 25 mg every 2 weeks, which she tolerates well.

When her beloved calico cat passes away, Ms. B experiences intense anxiety. Ms. B’s friend tells her she “needs some Valium,” but her psychiatrist, case manager, and the other patients in her dual-diagnosis group are not sure this is a good idea.

Benzodiazepines

Pros. There are multiple legitimate uses of benzodiazepines in general medicine and psychiatric practice, based upon their considerable sedative/hypnotic, anxiolytic, anticonvulsant, and muscle-relaxant properties (Table 1).¹

Recommendations regarding benzodiazepine use for anxious patients with a history of SUD are not clear-cut. First, it often is difficult to determine whether the patient truly has an anxiety disorder or is suffering anxiety symptoms secondary to substance use and/or withdrawal. In addition, even if a diagnosis of a separate anxiety disorder is established, psychiatrists debate how to treat such patients. Some clinicians maintain that benzodiazepines should be used only for acute detoxification, and that ongoing benzodiazepine use will lead to relapse or benzodiazepine dependence. However, in a prospective study of 545 alcohol use disorder (AUD) patients receiving benzodiazepines for anxiety disorders, Mueller et al² found no association—at 12 months or at 12 years—between benzodiazepine use and AUD recurrence. Furthermore, there was no difference in benzodiazepine usage when comparing patients with and without an AUD.³

Table 1

Clinical uses of benzodiazepines

Cons. Although widely prescribed—and despite their efficacy in numerous conditions— both acute or long-term benzodiazepine use frequently causes adverse effects.⁴ Patients may develop tolerance, which can lead to escalating dosages and/or to withdrawal symptoms when patients attempt to cut back. Benzodiazepines eventually become ineffective for sleep, and continued use can cause rebound insomnia. Also, with many patients taking benzodiazepines long-term, clinicians struggle to differentiate between “real” anxiety symptoms and subtle states of withdrawal from fluctuating benzodiazepine blood levels.⁵

Geriatric patients who take benzodiazepines are at risk for falls and hip fractures.⁴ Although older dementia patients are at particular risk for cognitive problems— including frank delirium—secondary to benzodiazepine use, patients of all ages are susceptible to these medications’ deleterious neurocognitive effects.

Benzodiazepines can lead to excessive sedation, thereby impairing performance at work or school, and have been implicated as a cause of motor vehicle accidents.⁶ Finally, a serious drawback to benzodiazepine use is possible lethality in overdose, especially when combined with alcohol.

Benzodiazepine prescribing should not be taken lightly. Always analyze the difference between benzodiazepines’ well-documented efficacy and their adverse effect profile. This risk-benefit analysis becomes much more complex for patients with SUDs.

Special considerations. Patients at higher risk for benzodiazepine abuse include those with:

• severe alcohol dependence (ie, long-term use, drinking since a young age [“Type II”])
• intravenous drug use
• comorbid alcoholism and antisocial personality disorder.^7,8

Exercise special caution when considering benzodiazepines for patients with severe psychiatric illness such as schizophrenia-spectrum disorders, bipolar disorder, or severe depression. Patients with schizophrenia have high rates of alcohol, cocaine, cannabis, and benzodiazepine abuse.^9,10 Bipolar disorder patients show similar vulnerability—up to 56% of patients screen positive for substance abuse or dependence.¹¹ Vulnerability to addiction in severely ill psychiatric patients is thought to be related to several factors, including:

• use of drugs as self-medication
• genetic predisposition
• environment/lifestyle that supports substance abuse
• neurobiologic deficits that lead to lack of inhibition of reward-seeking behaviors.¹¹

Bipolar disorder patients in particular score high on measures of sensation seeking, which leaves them vulnerable to abusing all classes of substances.¹²

In a 6-year study of 203 patients with severe psychiatric illnesses and SUDs, Brunette et al¹³ found that these patients were 2.5 times more likely than patients with severe psychiatric illness alone to abuse prescribed benzodiazepines. In an analysis of Medicaid records, Clark et al¹⁴ found similar vulnerability in patients with major depressive disorder (MDD) and SUD. Not only did these patients show a higher rate of benzodiazepine use than patients with MDD without SUD, but the dual-diagnosis group also gravitated toward more addictive high-potency/fast-acting benzodiazepines, such as alprazolam, estazolam, or triazolam.

Case discussion/suggestions. Initially, Mr. A may seem to be an appropriate candidate for closely monitored benzodiazepine use. However, he shows a pattern of misuse, likely related to his history of severe alcohol dependence and alprazolam use. This benzodiazepine is fast-acting and has a short half-life, and thus is highly reinforcing.

Similarly, Ms. B might benefit from benzodiazepine treatment. However, her history of schizophrenia and alcohol abuse makes her a risky candidate, and alternative treatments for anxiety symptoms should be considered. If prescribed at all, a benzodiazepine should be used only short-term (eg, 1 to 2 weeks).

In general, avoid prescribing benzodiazepines to most patients who have an ongoing or past SUD.¹⁵ Consider making an exception for SUD patients with comorbid anxiety disorders, with close monitoring of their benzodiazepine use. Clonazepam, chlordiazepoxide, clorazepate, and oxazepam may be less reinforcing for SUD patients than diazepam, lorazepam, alprazolam, estazolam, or triazolam.^7,16 The drawbacks of benzodiazepines, especially in the situations described above, point to the need to find alternative treatments (Table 2).¹⁷ Keep in mind nonpharmacologic options, which completely avoid the risks of medication misuse and diversion. Cognitive-behavioral therapy (CBT), for instance, has well-documented efficacy in treating insomnia and anxiety disorders.^18,19

Table 2

Alternatives to benzodiazepines for anxiety and/or insomnia

CASE 3 Adult ADHD and marijuana use

Mr. C, age 30, presents to a psychiatrist with ongoing complaints of inattention, fatigue, and difficulty staying organized. A self-report screen yields symptoms consistent with adult attention-deficit/hyperactivity disorder (ADHD). Mr. C’s school and job history and collateral history from his wife appear to corroborate his assertion that his symptoms have been lifelong. He later admits to regular marijuana use. After further discussion and full evaluation of his substance use, Mr. C is started on bupropion, titrated to 300 mg/d. After 2 months, despite faithful attendance at appointments and openness about his continued marijuana use, Mr. C’s symptoms remain unchanged. He asks about atomoxetine.

Stimulants

Pros. Despite many clinicians’ hesitance to prescribe controlled substances to patients with SUDs, psychostimulants should be considered in a variety of scenarios. Although nonstimulant options are available, stimulants consistently have demonstrated superior efficacy over other treatments and remain first-line agents for adult ADHD.²⁰ Methylphenidate, mixed amphetamine salts, lisdexamfetamine, and atomoxetine are FDA-approved for adult ADHD. Both stimulant classes (methylphenidate and amphetamine-based products) are equally effective for ADHD. In addition, stimulants are used to treat narcolepsy, cognitive disorders such as traumatic brain injury, and as augmentation to antidepressants for MDD.

ADHD affects 5% to 12% of children, and >60% of patients remain symptomatic into adulthood and require continued treatment.²¹ In particular, problematic inattention may persist throughout adulthood. ADHD does not appear to be an independent risk factor for SUDs in children and adolescents.²² However, substance use increases sharply as ADHD patients enter late adolescence and adulthood, and eventually becomes a problem for 20% of adolescents and adults with ADHD. Conversely, 17% to 50% of patients with alcohol, cocaine, or opioid dependence have co-occurring ADHD.²³

Withholding ADHD treatment based on concerns about future or increased current substance abuse is unfounded. A meta-analysis of 6 studies that included 674 medicated and 360 unmedicated patients with ADHD who were followed at least 4 years demonstrated that childhood treatment of ADHD with stimulants reduces the risk of developing alcohol and other drug disorders in adulthood.²⁴ Regarding the effect stimulants have on active substance use, a 12-week, double-blind, randomized controlled trial of 48 cocaine-dependent adults with ADHD showed methylphenidate did not change cocaine abuse or craving, but did improve ADHD symptoms.²⁵

Clinicians also must assess whether untreated ADHD symptoms impair patients’ work or other activities. Driving is a particular concern because ADHD is associated with risky driving habits, motor vehicle accidents, traffic violations, and driving license suspensions.²⁶ In a study that administered cognitive tests to 27 adults with ADHD, methylphenidate treatment improved cognitive performance related to driving (eg, better visual-motor coordination under high-stress conditions, improved visual orientation, and sustained visual attention).²⁷ It is likely this effect could be generalized to other activities where safety is important. Finally, appropriate stimulant treatment may improve participation in rehabilitative programs.

Cons. Despite their positive effects, stimulants can have adverse effects and consequences.²⁸ In routinely prescribed dosages, methylphenidate and amphetamines can cause symptoms related to sympathetic activation, including anxiety, tics, anorexia/ weight loss, and sleep disturbance. A 5-year study of 79 school-age children prescribed methylphenidate, dextroamphetamine, or pemoline, which is no longer available in the United States, showed a significant association between adherence to stimulants and persistence of physiological (eg, headaches, insomnia, anorexia) and mood-related (eg, irritability, dysphoria) side effects.²⁹ Stimulants’ sympathomimetic properties also can lead to dangerous drug-drug interactions with monoamine oxidase inhibitors. For both methylphenidate and amphetamines, overdose can lead to seizures, cardiac toxicity, dysrhythmias, and hyperthermia. All stimulants carry an FDA “black-box” warning that lists increased risk of cardiac complications, sudden death, and psychiatric complications such as psychosis or mania.³⁰

Special considerations. All stimulants have potential for diversion or abuse. Pay close attention to these issues, especially in vulnerable populations and situations where rates of abuse and diversion are elevated. Among college students, white patients, fraternity/sorority members, and individuals with lower grade point averages may be at higher risk for nonmedical stimulant use.³¹ Adults who misuse or divert stimulants commonly have a history of substance abuse and conduct disorder.³² Short-acting stimulants are abused 4 times more often than extended-release preparations.³³

If your ADHD patient has active substance use, be clear that continued substance use is likely to limit stimulants’ effectiveness. In patients who are actively using substances, it will be difficult to disentangle apparent nonresponse to stimulants from the negative cognitive effects of substance use.

Case discussion/suggestions. As Mr. C’s case illustrates, there are alternatives to stimulants for ADHD. For example, atomoxetine, a selective norepinephrine reuptake inhibitor, may be considered a first-line agent in patients with mostly inattentive ADHD symptoms and comorbid stimulant abuse, or for those in whom stimulants cause adverse effects such as mood lability or tics.³⁴ Other alternatives to stimulants are listed in Table 3.³⁵

Because Mr. C did not respond to bupropion, which presumably was tried first because of his ongoing substance use, he asked about atomoxetine. This agent is not addictive and there is no evidence that it leads to or exacerbates substance use. Depending on Mr. C’s symptom profile, atomoxetine might be a good choice. Continued monitoring of his marijuana use and frequent assessment of his motivation to quit are necessary. Psychoeducation about the cognitive effects of marijuana, including inattention and poor concentration, is important.

If Mr. C does not respond to atomoxetine, his psychiatrist will face a difficult decision. Setting Mr. C’s marijuana use aside, symptoms that do not respond to atomoxetine or a second-line agent are likely to respond to a stimulant. However, several issues must be addressed. If Mr. C’s motivation to stop using marijuana is low, how motivated is he to improve his ADHD symptoms? Next, would marijuana’s depressive/blunting effects counteract the anticipated benefit of a stimulant? Also, what is the risk that Mr. C might sell or exchange his stimulants to obtain marijuana? Assessing these complicated questions is key. Another important factor in Mr. C’s case is his wife’s involvement. Does she monitor his marijuana use? Would she be willing to supervise Mr. C’s stimulant use, and would he allow it?

Past or present SUDs are not an absolute contraindication to stimulant use. You should affirm the diagnosis and identify target symptoms. Consider nonstimulant alternatives if appropriate.

Table 3

Alternatives to stimulants for ADHD

Legal liabilities

Being aware of the medicolegal issues of benzodiazepine and/or stimulant prescribing is crucial because a court may find a psychiatrist liable for negative outcomes (eg, suicide) when controlled substances are prescribed to a patient with a history of addiction.³⁶ The most prudent course is to weigh the pros and cons for each patient individually, taking into consideration the factors described above.⁸ This is consistent with guidelines from the American Psychiatric Association and the British Association for Psychopharmacology,³⁷ both of which call for extreme caution in these cases.

Educate patients and caregivers about the risks of taking a controlled substance, including misuse, diversion, and theft. Provide and document explicit instructions that the patient will receive stimulants from only a single provider. Remind patients that state and federal authorities closely track controlled medications. Finally, a “stimulant contract” or “benzodiazepine contract,” similar to a pain or narcotic contact, may be useful to formally document discussions about appropriate medication use.

Related Resources

• National Institute on Drug Abuse. Prescription drugs: abuse and addiction. Research Report Series, 2005. http://drugabuse.gov/ResearchReports/Prescription/Prescription.html.
• Galanter M, Kleber HD. The American Psychiatric Publishing textbook of substance abuse treatment. 4th ed. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, others
• Chlordiazepoxide • Librium
• Clonazepam • Klonopin
• Clonidine • Catapres
• Clorazepate • Tranxene
• Dextroamphetamine • Dexedrine
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Doxepin • Silenor
• Estazolam • ProSom
• Gabapentin • Neurontin
• Guanfacine • Tenex, Intuniv
• Lisdexamfetamine • Vyvanse
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta, others
• Mirtazapine • Remeron
• Mixed amphetamine salts • Adderall
• Modafinil • Provigil
• Oxazepam • Serax
• Pemoline • Cylert
• Propranolol • Inderal
• Trazodone • Desyrel, Oleptro
• Triazolam • Halcion

Disclosures

Dr. Casher is a speaker for AstraZeneca and Pfizer Inc.

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

Although benzodiazepines and stimulants have well-documented efficacy for numerous psychiatric disorders, psychiatrists hesitate to prescribe these medications to patients with substance use disorders (SUDs)—even to those with a comorbid condition that likely would respond to a benzodiazepine or stimulant—because of risk of abuse or dependence. Conventional practice typically has focused on treating active substance use first rather than using simultaneous treatments. Prejudice, fear, and misinformation can influence this decision.

We believe these cases lie on a continuum. At one extreme, ignoring a past or present SUD may lead a remitted patient toward relapse, or further delay recovery for an active user. At the other end, psychiatrists who overreact to a remote history of substance use may deprive patients of legitimate pharmacologic symptom relief. Most cases lie somewhere in the middle.

A literature review does not support the assertion that the use of these medications leads to future substance use or worsens active use, especially for stimulants. In fact, stepwise—as opposed to concurrent—treatment for both conditions actually may delay recovery and increase patients’ risk for morbidity.

We outline issues involved in these complex clinical situations, point out controversies, review relevant research data, and offer guidelines for treatment.

CASE 1 Panic disorder in sobriety

Since he was a teen, Mr. A, age 51, drank heavily, which cost him jobs and relationships. After being convicted for driving under the influence, he was court-ordered to attend a rehabilitation facility, where, as he describes it, he “finally turned [his] life around.” He followed up residential treatment with regular attendance at Alcoholics Anonymous meetings.

After 1 year of sobriety, Mr. A develops increasingly frequent episodes of intense anxiety with sweating, nausea, chest pain, and hyperventilation and is diagnosed with panic disorder. His internist prescribes alprazolam, 0.5 mg 3 times a day, which provides some symptom relief, and refers him for follow-up psychiatric care. At his first visit, Mr. A confides to his psychiatrist that he is taking much more than the prescribed dosage of alprazolam, even when he is not experiencing anxiety, and is contemplating “buying it on the street” if his dosage is not raised to “at least 3 mg 3 times a day.”

CASE 2 Anxiety in controlled psychosis

Ms. B, age 40, had her first psychotic break at age 18 and was diagnosed with schizophrenia. Since then, she has had multiple psychiatric hospitalizations, usually presenting with auditory hallucinations and a recurring delusion that the person who calls herself Ms. B’s mother is really an actress “playing” her mother. At times this delusion has led Ms. B to attack her “imposter” mother. Over several years Ms. B began to drink heavily, but recently achieved a few months of sobriety by attending dual-diagnosis groups at her local community mental health center and individual psychotherapy sessions with her case manager. Fortunately, Ms. B’s psychosis has been stabilized with risperidone long-acting injection, 25 mg every 2 weeks, which she tolerates well.

When her beloved calico cat passes away, Ms. B experiences intense anxiety. Ms. B’s friend tells her she “needs some Valium,” but her psychiatrist, case manager, and the other patients in her dual-diagnosis group are not sure this is a good idea.

Benzodiazepines

Pros. There are multiple legitimate uses of benzodiazepines in general medicine and psychiatric practice, based upon their considerable sedative/hypnotic, anxiolytic, anticonvulsant, and muscle-relaxant properties (Table 1).¹

Recommendations regarding benzodiazepine use for anxious patients with a history of SUD are not clear-cut. First, it often is difficult to determine whether the patient truly has an anxiety disorder or is suffering anxiety symptoms secondary to substance use and/or withdrawal. In addition, even if a diagnosis of a separate anxiety disorder is established, psychiatrists debate how to treat such patients. Some clinicians maintain that benzodiazepines should be used only for acute detoxification, and that ongoing benzodiazepine use will lead to relapse or benzodiazepine dependence. However, in a prospective study of 545 alcohol use disorder (AUD) patients receiving benzodiazepines for anxiety disorders, Mueller et al² found no association—at 12 months or at 12 years—between benzodiazepine use and AUD recurrence. Furthermore, there was no difference in benzodiazepine usage when comparing patients with and without an AUD.³

Table 1

Clinical uses of benzodiazepines

Cons. Although widely prescribed—and despite their efficacy in numerous conditions— both acute or long-term benzodiazepine use frequently causes adverse effects.⁴ Patients may develop tolerance, which can lead to escalating dosages and/or to withdrawal symptoms when patients attempt to cut back. Benzodiazepines eventually become ineffective for sleep, and continued use can cause rebound insomnia. Also, with many patients taking benzodiazepines long-term, clinicians struggle to differentiate between “real” anxiety symptoms and subtle states of withdrawal from fluctuating benzodiazepine blood levels.⁵

Geriatric patients who take benzodiazepines are at risk for falls and hip fractures.⁴ Although older dementia patients are at particular risk for cognitive problems— including frank delirium—secondary to benzodiazepine use, patients of all ages are susceptible to these medications’ deleterious neurocognitive effects.

Benzodiazepines can lead to excessive sedation, thereby impairing performance at work or school, and have been implicated as a cause of motor vehicle accidents.⁶ Finally, a serious drawback to benzodiazepine use is possible lethality in overdose, especially when combined with alcohol.

Benzodiazepine prescribing should not be taken lightly. Always analyze the difference between benzodiazepines’ well-documented efficacy and their adverse effect profile. This risk-benefit analysis becomes much more complex for patients with SUDs.

Special considerations. Patients at higher risk for benzodiazepine abuse include those with:

• severe alcohol dependence (ie, long-term use, drinking since a young age [“Type II”])
• intravenous drug use
• comorbid alcoholism and antisocial personality disorder.^7,8

Exercise special caution when considering benzodiazepines for patients with severe psychiatric illness such as schizophrenia-spectrum disorders, bipolar disorder, or severe depression. Patients with schizophrenia have high rates of alcohol, cocaine, cannabis, and benzodiazepine abuse.^9,10 Bipolar disorder patients show similar vulnerability—up to 56% of patients screen positive for substance abuse or dependence.¹¹ Vulnerability to addiction in severely ill psychiatric patients is thought to be related to several factors, including:

• use of drugs as self-medication
• genetic predisposition
• environment/lifestyle that supports substance abuse
• neurobiologic deficits that lead to lack of inhibition of reward-seeking behaviors.¹¹

Bipolar disorder patients in particular score high on measures of sensation seeking, which leaves them vulnerable to abusing all classes of substances.¹²

In a 6-year study of 203 patients with severe psychiatric illnesses and SUDs, Brunette et al¹³ found that these patients were 2.5 times more likely than patients with severe psychiatric illness alone to abuse prescribed benzodiazepines. In an analysis of Medicaid records, Clark et al¹⁴ found similar vulnerability in patients with major depressive disorder (MDD) and SUD. Not only did these patients show a higher rate of benzodiazepine use than patients with MDD without SUD, but the dual-diagnosis group also gravitated toward more addictive high-potency/fast-acting benzodiazepines, such as alprazolam, estazolam, or triazolam.

Case discussion/suggestions. Initially, Mr. A may seem to be an appropriate candidate for closely monitored benzodiazepine use. However, he shows a pattern of misuse, likely related to his history of severe alcohol dependence and alprazolam use. This benzodiazepine is fast-acting and has a short half-life, and thus is highly reinforcing.

Similarly, Ms. B might benefit from benzodiazepine treatment. However, her history of schizophrenia and alcohol abuse makes her a risky candidate, and alternative treatments for anxiety symptoms should be considered. If prescribed at all, a benzodiazepine should be used only short-term (eg, 1 to 2 weeks).

In general, avoid prescribing benzodiazepines to most patients who have an ongoing or past SUD.¹⁵ Consider making an exception for SUD patients with comorbid anxiety disorders, with close monitoring of their benzodiazepine use. Clonazepam, chlordiazepoxide, clorazepate, and oxazepam may be less reinforcing for SUD patients than diazepam, lorazepam, alprazolam, estazolam, or triazolam.^7,16 The drawbacks of benzodiazepines, especially in the situations described above, point to the need to find alternative treatments (Table 2).¹⁷ Keep in mind nonpharmacologic options, which completely avoid the risks of medication misuse and diversion. Cognitive-behavioral therapy (CBT), for instance, has well-documented efficacy in treating insomnia and anxiety disorders.^18,19

Table 2

Alternatives to benzodiazepines for anxiety and/or insomnia

CASE 3 Adult ADHD and marijuana use

Mr. C, age 30, presents to a psychiatrist with ongoing complaints of inattention, fatigue, and difficulty staying organized. A self-report screen yields symptoms consistent with adult attention-deficit/hyperactivity disorder (ADHD). Mr. C’s school and job history and collateral history from his wife appear to corroborate his assertion that his symptoms have been lifelong. He later admits to regular marijuana use. After further discussion and full evaluation of his substance use, Mr. C is started on bupropion, titrated to 300 mg/d. After 2 months, despite faithful attendance at appointments and openness about his continued marijuana use, Mr. C’s symptoms remain unchanged. He asks about atomoxetine.

Stimulants

Pros. Despite many clinicians’ hesitance to prescribe controlled substances to patients with SUDs, psychostimulants should be considered in a variety of scenarios. Although nonstimulant options are available, stimulants consistently have demonstrated superior efficacy over other treatments and remain first-line agents for adult ADHD.²⁰ Methylphenidate, mixed amphetamine salts, lisdexamfetamine, and atomoxetine are FDA-approved for adult ADHD. Both stimulant classes (methylphenidate and amphetamine-based products) are equally effective for ADHD. In addition, stimulants are used to treat narcolepsy, cognitive disorders such as traumatic brain injury, and as augmentation to antidepressants for MDD.

ADHD affects 5% to 12% of children, and >60% of patients remain symptomatic into adulthood and require continued treatment.²¹ In particular, problematic inattention may persist throughout adulthood. ADHD does not appear to be an independent risk factor for SUDs in children and adolescents.²² However, substance use increases sharply as ADHD patients enter late adolescence and adulthood, and eventually becomes a problem for 20% of adolescents and adults with ADHD. Conversely, 17% to 50% of patients with alcohol, cocaine, or opioid dependence have co-occurring ADHD.²³

Withholding ADHD treatment based on concerns about future or increased current substance abuse is unfounded. A meta-analysis of 6 studies that included 674 medicated and 360 unmedicated patients with ADHD who were followed at least 4 years demonstrated that childhood treatment of ADHD with stimulants reduces the risk of developing alcohol and other drug disorders in adulthood.²⁴ Regarding the effect stimulants have on active substance use, a 12-week, double-blind, randomized controlled trial of 48 cocaine-dependent adults with ADHD showed methylphenidate did not change cocaine abuse or craving, but did improve ADHD symptoms.²⁵

Clinicians also must assess whether untreated ADHD symptoms impair patients’ work or other activities. Driving is a particular concern because ADHD is associated with risky driving habits, motor vehicle accidents, traffic violations, and driving license suspensions.²⁶ In a study that administered cognitive tests to 27 adults with ADHD, methylphenidate treatment improved cognitive performance related to driving (eg, better visual-motor coordination under high-stress conditions, improved visual orientation, and sustained visual attention).²⁷ It is likely this effect could be generalized to other activities where safety is important. Finally, appropriate stimulant treatment may improve participation in rehabilitative programs.

Cons. Despite their positive effects, stimulants can have adverse effects and consequences.²⁸ In routinely prescribed dosages, methylphenidate and amphetamines can cause symptoms related to sympathetic activation, including anxiety, tics, anorexia/ weight loss, and sleep disturbance. A 5-year study of 79 school-age children prescribed methylphenidate, dextroamphetamine, or pemoline, which is no longer available in the United States, showed a significant association between adherence to stimulants and persistence of physiological (eg, headaches, insomnia, anorexia) and mood-related (eg, irritability, dysphoria) side effects.²⁹ Stimulants’ sympathomimetic properties also can lead to dangerous drug-drug interactions with monoamine oxidase inhibitors. For both methylphenidate and amphetamines, overdose can lead to seizures, cardiac toxicity, dysrhythmias, and hyperthermia. All stimulants carry an FDA “black-box” warning that lists increased risk of cardiac complications, sudden death, and psychiatric complications such as psychosis or mania.³⁰

Special considerations. All stimulants have potential for diversion or abuse. Pay close attention to these issues, especially in vulnerable populations and situations where rates of abuse and diversion are elevated. Among college students, white patients, fraternity/sorority members, and individuals with lower grade point averages may be at higher risk for nonmedical stimulant use.³¹ Adults who misuse or divert stimulants commonly have a history of substance abuse and conduct disorder.³² Short-acting stimulants are abused 4 times more often than extended-release preparations.³³

If your ADHD patient has active substance use, be clear that continued substance use is likely to limit stimulants’ effectiveness. In patients who are actively using substances, it will be difficult to disentangle apparent nonresponse to stimulants from the negative cognitive effects of substance use.

Case discussion/suggestions. As Mr. C’s case illustrates, there are alternatives to stimulants for ADHD. For example, atomoxetine, a selective norepinephrine reuptake inhibitor, may be considered a first-line agent in patients with mostly inattentive ADHD symptoms and comorbid stimulant abuse, or for those in whom stimulants cause adverse effects such as mood lability or tics.³⁴ Other alternatives to stimulants are listed in Table 3.³⁵

Because Mr. C did not respond to bupropion, which presumably was tried first because of his ongoing substance use, he asked about atomoxetine. This agent is not addictive and there is no evidence that it leads to or exacerbates substance use. Depending on Mr. C’s symptom profile, atomoxetine might be a good choice. Continued monitoring of his marijuana use and frequent assessment of his motivation to quit are necessary. Psychoeducation about the cognitive effects of marijuana, including inattention and poor concentration, is important.

If Mr. C does not respond to atomoxetine, his psychiatrist will face a difficult decision. Setting Mr. C’s marijuana use aside, symptoms that do not respond to atomoxetine or a second-line agent are likely to respond to a stimulant. However, several issues must be addressed. If Mr. C’s motivation to stop using marijuana is low, how motivated is he to improve his ADHD symptoms? Next, would marijuana’s depressive/blunting effects counteract the anticipated benefit of a stimulant? Also, what is the risk that Mr. C might sell or exchange his stimulants to obtain marijuana? Assessing these complicated questions is key. Another important factor in Mr. C’s case is his wife’s involvement. Does she monitor his marijuana use? Would she be willing to supervise Mr. C’s stimulant use, and would he allow it?

Past or present SUDs are not an absolute contraindication to stimulant use. You should affirm the diagnosis and identify target symptoms. Consider nonstimulant alternatives if appropriate.

Table 3

Alternatives to stimulants for ADHD

Legal liabilities

Being aware of the medicolegal issues of benzodiazepine and/or stimulant prescribing is crucial because a court may find a psychiatrist liable for negative outcomes (eg, suicide) when controlled substances are prescribed to a patient with a history of addiction.³⁶ The most prudent course is to weigh the pros and cons for each patient individually, taking into consideration the factors described above.⁸ This is consistent with guidelines from the American Psychiatric Association and the British Association for Psychopharmacology,³⁷ both of which call for extreme caution in these cases.

Educate patients and caregivers about the risks of taking a controlled substance, including misuse, diversion, and theft. Provide and document explicit instructions that the patient will receive stimulants from only a single provider. Remind patients that state and federal authorities closely track controlled medications. Finally, a “stimulant contract” or “benzodiazepine contract,” similar to a pain or narcotic contact, may be useful to formally document discussions about appropriate medication use.

Related Resources

• National Institute on Drug Abuse. Prescription drugs: abuse and addiction. Research Report Series, 2005. http://drugabuse.gov/ResearchReports/Prescription/Prescription.html.
• Galanter M, Kleber HD. The American Psychiatric Publishing textbook of substance abuse treatment. 4th ed. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, others
• Chlordiazepoxide • Librium
• Clonazepam • Klonopin
• Clonidine • Catapres
• Clorazepate • Tranxene
• Dextroamphetamine • Dexedrine
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Doxepin • Silenor
• Estazolam • ProSom
• Gabapentin • Neurontin
• Guanfacine • Tenex, Intuniv
• Lisdexamfetamine • Vyvanse
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta, others
• Mirtazapine • Remeron
• Mixed amphetamine salts • Adderall
• Modafinil • Provigil
• Oxazepam • Serax
• Pemoline • Cylert
• Propranolol • Inderal
• Trazodone • Desyrel, Oleptro
• Triazolam • Halcion

Disclosures

Dr. Casher is a speaker for AstraZeneca and Pfizer Inc.

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

Although benzodiazepines and stimulants have well-documented efficacy for numerous psychiatric disorders, psychiatrists hesitate to prescribe these medications to patients with substance use disorders (SUDs)—even to those with a comorbid condition that likely would respond to a benzodiazepine or stimulant—because of risk of abuse or dependence. Conventional practice typically has focused on treating active substance use first rather than using simultaneous treatments. Prejudice, fear, and misinformation can influence this decision.

We believe these cases lie on a continuum. At one extreme, ignoring a past or present SUD may lead a remitted patient toward relapse, or further delay recovery for an active user. At the other end, psychiatrists who overreact to a remote history of substance use may deprive patients of legitimate pharmacologic symptom relief. Most cases lie somewhere in the middle.

A literature review does not support the assertion that the use of these medications leads to future substance use or worsens active use, especially for stimulants. In fact, stepwise—as opposed to concurrent—treatment for both conditions actually may delay recovery and increase patients’ risk for morbidity.

We outline issues involved in these complex clinical situations, point out controversies, review relevant research data, and offer guidelines for treatment.

CASE 1 Panic disorder in sobriety

Since he was a teen, Mr. A, age 51, drank heavily, which cost him jobs and relationships. After being convicted for driving under the influence, he was court-ordered to attend a rehabilitation facility, where, as he describes it, he “finally turned [his] life around.” He followed up residential treatment with regular attendance at Alcoholics Anonymous meetings.

After 1 year of sobriety, Mr. A develops increasingly frequent episodes of intense anxiety with sweating, nausea, chest pain, and hyperventilation and is diagnosed with panic disorder. His internist prescribes alprazolam, 0.5 mg 3 times a day, which provides some symptom relief, and refers him for follow-up psychiatric care. At his first visit, Mr. A confides to his psychiatrist that he is taking much more than the prescribed dosage of alprazolam, even when he is not experiencing anxiety, and is contemplating “buying it on the street” if his dosage is not raised to “at least 3 mg 3 times a day.”

CASE 2 Anxiety in controlled psychosis

Ms. B, age 40, had her first psychotic break at age 18 and was diagnosed with schizophrenia. Since then, she has had multiple psychiatric hospitalizations, usually presenting with auditory hallucinations and a recurring delusion that the person who calls herself Ms. B’s mother is really an actress “playing” her mother. At times this delusion has led Ms. B to attack her “imposter” mother. Over several years Ms. B began to drink heavily, but recently achieved a few months of sobriety by attending dual-diagnosis groups at her local community mental health center and individual psychotherapy sessions with her case manager. Fortunately, Ms. B’s psychosis has been stabilized with risperidone long-acting injection, 25 mg every 2 weeks, which she tolerates well.

When her beloved calico cat passes away, Ms. B experiences intense anxiety. Ms. B’s friend tells her she “needs some Valium,” but her psychiatrist, case manager, and the other patients in her dual-diagnosis group are not sure this is a good idea.

Benzodiazepines

Pros. There are multiple legitimate uses of benzodiazepines in general medicine and psychiatric practice, based upon their considerable sedative/hypnotic, anxiolytic, anticonvulsant, and muscle-relaxant properties (Table 1).¹

Recommendations regarding benzodiazepine use for anxious patients with a history of SUD are not clear-cut. First, it often is difficult to determine whether the patient truly has an anxiety disorder or is suffering anxiety symptoms secondary to substance use and/or withdrawal. In addition, even if a diagnosis of a separate anxiety disorder is established, psychiatrists debate how to treat such patients. Some clinicians maintain that benzodiazepines should be used only for acute detoxification, and that ongoing benzodiazepine use will lead to relapse or benzodiazepine dependence. However, in a prospective study of 545 alcohol use disorder (AUD) patients receiving benzodiazepines for anxiety disorders, Mueller et al² found no association—at 12 months or at 12 years—between benzodiazepine use and AUD recurrence. Furthermore, there was no difference in benzodiazepine usage when comparing patients with and without an AUD.³

Table 1

Clinical uses of benzodiazepines

Cons. Although widely prescribed—and despite their efficacy in numerous conditions— both acute or long-term benzodiazepine use frequently causes adverse effects.⁴ Patients may develop tolerance, which can lead to escalating dosages and/or to withdrawal symptoms when patients attempt to cut back. Benzodiazepines eventually become ineffective for sleep, and continued use can cause rebound insomnia. Also, with many patients taking benzodiazepines long-term, clinicians struggle to differentiate between “real” anxiety symptoms and subtle states of withdrawal from fluctuating benzodiazepine blood levels.⁵

Geriatric patients who take benzodiazepines are at risk for falls and hip fractures.⁴ Although older dementia patients are at particular risk for cognitive problems— including frank delirium—secondary to benzodiazepine use, patients of all ages are susceptible to these medications’ deleterious neurocognitive effects.

Benzodiazepines can lead to excessive sedation, thereby impairing performance at work or school, and have been implicated as a cause of motor vehicle accidents.⁶ Finally, a serious drawback to benzodiazepine use is possible lethality in overdose, especially when combined with alcohol.

Benzodiazepine prescribing should not be taken lightly. Always analyze the difference between benzodiazepines’ well-documented efficacy and their adverse effect profile. This risk-benefit analysis becomes much more complex for patients with SUDs.

Special considerations. Patients at higher risk for benzodiazepine abuse include those with:

• severe alcohol dependence (ie, long-term use, drinking since a young age [“Type II”])
• intravenous drug use
• comorbid alcoholism and antisocial personality disorder.^7,8

Exercise special caution when considering benzodiazepines for patients with severe psychiatric illness such as schizophrenia-spectrum disorders, bipolar disorder, or severe depression. Patients with schizophrenia have high rates of alcohol, cocaine, cannabis, and benzodiazepine abuse.^9,10 Bipolar disorder patients show similar vulnerability—up to 56% of patients screen positive for substance abuse or dependence.¹¹ Vulnerability to addiction in severely ill psychiatric patients is thought to be related to several factors, including:

• use of drugs as self-medication
• genetic predisposition
• environment/lifestyle that supports substance abuse
• neurobiologic deficits that lead to lack of inhibition of reward-seeking behaviors.¹¹

Bipolar disorder patients in particular score high on measures of sensation seeking, which leaves them vulnerable to abusing all classes of substances.¹²

In a 6-year study of 203 patients with severe psychiatric illnesses and SUDs, Brunette et al¹³ found that these patients were 2.5 times more likely than patients with severe psychiatric illness alone to abuse prescribed benzodiazepines. In an analysis of Medicaid records, Clark et al¹⁴ found similar vulnerability in patients with major depressive disorder (MDD) and SUD. Not only did these patients show a higher rate of benzodiazepine use than patients with MDD without SUD, but the dual-diagnosis group also gravitated toward more addictive high-potency/fast-acting benzodiazepines, such as alprazolam, estazolam, or triazolam.

Case discussion/suggestions. Initially, Mr. A may seem to be an appropriate candidate for closely monitored benzodiazepine use. However, he shows a pattern of misuse, likely related to his history of severe alcohol dependence and alprazolam use. This benzodiazepine is fast-acting and has a short half-life, and thus is highly reinforcing.

Similarly, Ms. B might benefit from benzodiazepine treatment. However, her history of schizophrenia and alcohol abuse makes her a risky candidate, and alternative treatments for anxiety symptoms should be considered. If prescribed at all, a benzodiazepine should be used only short-term (eg, 1 to 2 weeks).

In general, avoid prescribing benzodiazepines to most patients who have an ongoing or past SUD.¹⁵ Consider making an exception for SUD patients with comorbid anxiety disorders, with close monitoring of their benzodiazepine use. Clonazepam, chlordiazepoxide, clorazepate, and oxazepam may be less reinforcing for SUD patients than diazepam, lorazepam, alprazolam, estazolam, or triazolam.^7,16 The drawbacks of benzodiazepines, especially in the situations described above, point to the need to find alternative treatments (Table 2).¹⁷ Keep in mind nonpharmacologic options, which completely avoid the risks of medication misuse and diversion. Cognitive-behavioral therapy (CBT), for instance, has well-documented efficacy in treating insomnia and anxiety disorders.^18,19

Table 2

Alternatives to benzodiazepines for anxiety and/or insomnia

CASE 3 Adult ADHD and marijuana use

Mr. C, age 30, presents to a psychiatrist with ongoing complaints of inattention, fatigue, and difficulty staying organized. A self-report screen yields symptoms consistent with adult attention-deficit/hyperactivity disorder (ADHD). Mr. C’s school and job history and collateral history from his wife appear to corroborate his assertion that his symptoms have been lifelong. He later admits to regular marijuana use. After further discussion and full evaluation of his substance use, Mr. C is started on bupropion, titrated to 300 mg/d. After 2 months, despite faithful attendance at appointments and openness about his continued marijuana use, Mr. C’s symptoms remain unchanged. He asks about atomoxetine.

Stimulants

Pros. Despite many clinicians’ hesitance to prescribe controlled substances to patients with SUDs, psychostimulants should be considered in a variety of scenarios. Although nonstimulant options are available, stimulants consistently have demonstrated superior efficacy over other treatments and remain first-line agents for adult ADHD.²⁰ Methylphenidate, mixed amphetamine salts, lisdexamfetamine, and atomoxetine are FDA-approved for adult ADHD. Both stimulant classes (methylphenidate and amphetamine-based products) are equally effective for ADHD. In addition, stimulants are used to treat narcolepsy, cognitive disorders such as traumatic brain injury, and as augmentation to antidepressants for MDD.

ADHD affects 5% to 12% of children, and >60% of patients remain symptomatic into adulthood and require continued treatment.²¹ In particular, problematic inattention may persist throughout adulthood. ADHD does not appear to be an independent risk factor for SUDs in children and adolescents.²² However, substance use increases sharply as ADHD patients enter late adolescence and adulthood, and eventually becomes a problem for 20% of adolescents and adults with ADHD. Conversely, 17% to 50% of patients with alcohol, cocaine, or opioid dependence have co-occurring ADHD.²³

Withholding ADHD treatment based on concerns about future or increased current substance abuse is unfounded. A meta-analysis of 6 studies that included 674 medicated and 360 unmedicated patients with ADHD who were followed at least 4 years demonstrated that childhood treatment of ADHD with stimulants reduces the risk of developing alcohol and other drug disorders in adulthood.²⁴ Regarding the effect stimulants have on active substance use, a 12-week, double-blind, randomized controlled trial of 48 cocaine-dependent adults with ADHD showed methylphenidate did not change cocaine abuse or craving, but did improve ADHD symptoms.²⁵

Clinicians also must assess whether untreated ADHD symptoms impair patients’ work or other activities. Driving is a particular concern because ADHD is associated with risky driving habits, motor vehicle accidents, traffic violations, and driving license suspensions.²⁶ In a study that administered cognitive tests to 27 adults with ADHD, methylphenidate treatment improved cognitive performance related to driving (eg, better visual-motor coordination under high-stress conditions, improved visual orientation, and sustained visual attention).²⁷ It is likely this effect could be generalized to other activities where safety is important. Finally, appropriate stimulant treatment may improve participation in rehabilitative programs.

Cons. Despite their positive effects, stimulants can have adverse effects and consequences.²⁸ In routinely prescribed dosages, methylphenidate and amphetamines can cause symptoms related to sympathetic activation, including anxiety, tics, anorexia/ weight loss, and sleep disturbance. A 5-year study of 79 school-age children prescribed methylphenidate, dextroamphetamine, or pemoline, which is no longer available in the United States, showed a significant association between adherence to stimulants and persistence of physiological (eg, headaches, insomnia, anorexia) and mood-related (eg, irritability, dysphoria) side effects.²⁹ Stimulants’ sympathomimetic properties also can lead to dangerous drug-drug interactions with monoamine oxidase inhibitors. For both methylphenidate and amphetamines, overdose can lead to seizures, cardiac toxicity, dysrhythmias, and hyperthermia. All stimulants carry an FDA “black-box” warning that lists increased risk of cardiac complications, sudden death, and psychiatric complications such as psychosis or mania.³⁰

Special considerations. All stimulants have potential for diversion or abuse. Pay close attention to these issues, especially in vulnerable populations and situations where rates of abuse and diversion are elevated. Among college students, white patients, fraternity/sorority members, and individuals with lower grade point averages may be at higher risk for nonmedical stimulant use.³¹ Adults who misuse or divert stimulants commonly have a history of substance abuse and conduct disorder.³² Short-acting stimulants are abused 4 times more often than extended-release preparations.³³

If your ADHD patient has active substance use, be clear that continued substance use is likely to limit stimulants’ effectiveness. In patients who are actively using substances, it will be difficult to disentangle apparent nonresponse to stimulants from the negative cognitive effects of substance use.

Case discussion/suggestions. As Mr. C’s case illustrates, there are alternatives to stimulants for ADHD. For example, atomoxetine, a selective norepinephrine reuptake inhibitor, may be considered a first-line agent in patients with mostly inattentive ADHD symptoms and comorbid stimulant abuse, or for those in whom stimulants cause adverse effects such as mood lability or tics.³⁴ Other alternatives to stimulants are listed in Table 3.³⁵

Because Mr. C did not respond to bupropion, which presumably was tried first because of his ongoing substance use, he asked about atomoxetine. This agent is not addictive and there is no evidence that it leads to or exacerbates substance use. Depending on Mr. C’s symptom profile, atomoxetine might be a good choice. Continued monitoring of his marijuana use and frequent assessment of his motivation to quit are necessary. Psychoeducation about the cognitive effects of marijuana, including inattention and poor concentration, is important.

If Mr. C does not respond to atomoxetine, his psychiatrist will face a difficult decision. Setting Mr. C’s marijuana use aside, symptoms that do not respond to atomoxetine or a second-line agent are likely to respond to a stimulant. However, several issues must be addressed. If Mr. C’s motivation to stop using marijuana is low, how motivated is he to improve his ADHD symptoms? Next, would marijuana’s depressive/blunting effects counteract the anticipated benefit of a stimulant? Also, what is the risk that Mr. C might sell or exchange his stimulants to obtain marijuana? Assessing these complicated questions is key. Another important factor in Mr. C’s case is his wife’s involvement. Does she monitor his marijuana use? Would she be willing to supervise Mr. C’s stimulant use, and would he allow it?

Past or present SUDs are not an absolute contraindication to stimulant use. You should affirm the diagnosis and identify target symptoms. Consider nonstimulant alternatives if appropriate.

Table 3

Alternatives to stimulants for ADHD

Legal liabilities

Being aware of the medicolegal issues of benzodiazepine and/or stimulant prescribing is crucial because a court may find a psychiatrist liable for negative outcomes (eg, suicide) when controlled substances are prescribed to a patient with a history of addiction.³⁶ The most prudent course is to weigh the pros and cons for each patient individually, taking into consideration the factors described above.⁸ This is consistent with guidelines from the American Psychiatric Association and the British Association for Psychopharmacology,³⁷ both of which call for extreme caution in these cases.

Educate patients and caregivers about the risks of taking a controlled substance, including misuse, diversion, and theft. Provide and document explicit instructions that the patient will receive stimulants from only a single provider. Remind patients that state and federal authorities closely track controlled medications. Finally, a “stimulant contract” or “benzodiazepine contract,” similar to a pain or narcotic contact, may be useful to formally document discussions about appropriate medication use.

Related Resources

• National Institute on Drug Abuse. Prescription drugs: abuse and addiction. Research Report Series, 2005. http://drugabuse.gov/ResearchReports/Prescription/Prescription.html.
• Galanter M, Kleber HD. The American Psychiatric Publishing textbook of substance abuse treatment. 4th ed. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, others
• Chlordiazepoxide • Librium
• Clonazepam • Klonopin
• Clonidine • Catapres
• Clorazepate • Tranxene
• Dextroamphetamine • Dexedrine
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Doxepin • Silenor
• Estazolam • ProSom
• Gabapentin • Neurontin
• Guanfacine • Tenex, Intuniv
• Lisdexamfetamine • Vyvanse
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta, others
• Mirtazapine • Remeron
• Mixed amphetamine salts • Adderall
• Modafinil • Provigil
• Oxazepam • Serax
• Pemoline • Cylert
• Propranolol • Inderal
• Trazodone • Desyrel, Oleptro
• Triazolam • Halcion

Disclosures

Dr. Casher is a speaker for AstraZeneca and Pfizer Inc.

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