Current Psychiatry

Rating scales give psychiatrists an objective benchmark on which to base critical treatment decisions, but not all clinicians use them because they view scales as time-consuming and offering little clinical yield. However, any depression self-rating scale (Table) can yield valuable clinical information if you pay attention to 3 areas.

Table

Commonly used depression self-rating scales

1. Total score

The total score supplies patients with objective feedback on their symptom severity, supports your treatment recommendations, and provides a benchmark for clinical decision-making. This information can help you determine when:

• the patient has shown no or insufficient improvement and treatment should be changed
  
• the patient has improved enough to stay the course
  
• antidepressant treatment would not be helpful because the baseline score is within the normal range.
  

2. Individual items

Note items that stand out because the patient rated them very high or endorsed items such as suicidality. An item-by-item analysis can help you focus on symptoms the patient considers problematic and which could be treatment targets, such as severe insomnia or fatigue. Often you can detect a pattern in the results, such as if a patient displays strong somatization or has mostly depressive cognitions.

3. Approach to the scale

Observe the patient while he or she fills out the scale. Obsessive patients might take a long time to complete the scale be-cause they cannot decide which answer is correct and will argue with you about individual items. They may want to answer “2.5” instead of having to choose between 2 or 3. Patients with cognitive problems also might need a long time to complete the questionnaire, but don’t forget about possible marginal literacy. Narcissistic patients might refuse to take the test because it is “below” them to fill out a scale that surely cannot capture their specialness.

Used in these 3 ways, scales are not a burden but an opportunity to engage your patient and to practice patient-centered medicine, even during brief clinical encounters.

Rating scales give psychiatrists an objective benchmark on which to base critical treatment decisions, but not all clinicians use them because they view scales as time-consuming and offering little clinical yield. However, any depression self-rating scale (Table) can yield valuable clinical information if you pay attention to 3 areas.

Table

Commonly used depression self-rating scales

1. Total score

The total score supplies patients with objective feedback on their symptom severity, supports your treatment recommendations, and provides a benchmark for clinical decision-making. This information can help you determine when:

• the patient has shown no or insufficient improvement and treatment should be changed
  
• the patient has improved enough to stay the course
  
• antidepressant treatment would not be helpful because the baseline score is within the normal range.
  

2. Individual items

Note items that stand out because the patient rated them very high or endorsed items such as suicidality. An item-by-item analysis can help you focus on symptoms the patient considers problematic and which could be treatment targets, such as severe insomnia or fatigue. Often you can detect a pattern in the results, such as if a patient displays strong somatization or has mostly depressive cognitions.

3. Approach to the scale

Observe the patient while he or she fills out the scale. Obsessive patients might take a long time to complete the scale be-cause they cannot decide which answer is correct and will argue with you about individual items. They may want to answer “2.5” instead of having to choose between 2 or 3. Patients with cognitive problems also might need a long time to complete the questionnaire, but don’t forget about possible marginal literacy. Narcissistic patients might refuse to take the test because it is “below” them to fill out a scale that surely cannot capture their specialness.

Used in these 3 ways, scales are not a burden but an opportunity to engage your patient and to practice patient-centered medicine, even during brief clinical encounters.

Rating scales give psychiatrists an objective benchmark on which to base critical treatment decisions, but not all clinicians use them because they view scales as time-consuming and offering little clinical yield. However, any depression self-rating scale (Table) can yield valuable clinical information if you pay attention to 3 areas.

Table

Commonly used depression self-rating scales

1. Total score

The total score supplies patients with objective feedback on their symptom severity, supports your treatment recommendations, and provides a benchmark for clinical decision-making. This information can help you determine when:

• the patient has shown no or insufficient improvement and treatment should be changed
  
• the patient has improved enough to stay the course
  
• antidepressant treatment would not be helpful because the baseline score is within the normal range.
  

2. Individual items

Note items that stand out because the patient rated them very high or endorsed items such as suicidality. An item-by-item analysis can help you focus on symptoms the patient considers problematic and which could be treatment targets, such as severe insomnia or fatigue. Often you can detect a pattern in the results, such as if a patient displays strong somatization or has mostly depressive cognitions.

3. Approach to the scale

Observe the patient while he or she fills out the scale. Obsessive patients might take a long time to complete the scale be-cause they cannot decide which answer is correct and will argue with you about individual items. They may want to answer “2.5” instead of having to choose between 2 or 3. Patients with cognitive problems also might need a long time to complete the questionnaire, but don’t forget about possible marginal literacy. Narcissistic patients might refuse to take the test because it is “below” them to fill out a scale that surely cannot capture their specialness.

Used in these 3 ways, scales are not a burden but an opportunity to engage your patient and to practice patient-centered medicine, even during brief clinical encounters.

I heartily agree with Dr. Henry Nasrallah’s stance about the treatment of chronically mentally ill individuals, specifically those with schizophrenia. I recently completed my psychiatry residency in Virginia. In addition to the consequences Dr. Nasrallah outlined in his editorial, I have identified a few additional disastrous effects of transferring care of severely mentally ill patients from state hospitals to the community service boards (CSBs).

Working in a hospital affiliated with a medical school meant that we took care of all indigent patients who were admitted. It is heartbreaking to spend weeks stabilizing a very ill patient and then send him or her back to the disastrous circumstances that often lead to the initial hospitalization. I saw patients discharged with appointments to CSBs that they had little chance of finding, getting to, or even remembering. These patients often were prescribed medications that I could not afford even with health insurance.

Discharged patients don’t fill prescriptions or they can’t remember medication schedules because they are too busy trying to survive. People who most need effective medicines have long ago become nonresponsive because of repeated periods of non-compliance.

Severely mentally ill persons do not have lobbyists in government; they are not likely to organize a march on Washington, DC. They have no voice, which is why their whimpers go unheard and unanswered.

Erica Bradshaw, MD
Staff psychiatrist
Inpatient psychiatry
Houston Veterans Administration Medical Center
Houston, TX

I heartily agree with Dr. Henry Nasrallah’s stance about the treatment of chronically mentally ill individuals, specifically those with schizophrenia. I recently completed my psychiatry residency in Virginia. In addition to the consequences Dr. Nasrallah outlined in his editorial, I have identified a few additional disastrous effects of transferring care of severely mentally ill patients from state hospitals to the community service boards (CSBs).

Working in a hospital affiliated with a medical school meant that we took care of all indigent patients who were admitted. It is heartbreaking to spend weeks stabilizing a very ill patient and then send him or her back to the disastrous circumstances that often lead to the initial hospitalization. I saw patients discharged with appointments to CSBs that they had little chance of finding, getting to, or even remembering. These patients often were prescribed medications that I could not afford even with health insurance.

Discharged patients don’t fill prescriptions or they can’t remember medication schedules because they are too busy trying to survive. People who most need effective medicines have long ago become nonresponsive because of repeated periods of non-compliance.

Severely mentally ill persons do not have lobbyists in government; they are not likely to organize a march on Washington, DC. They have no voice, which is why their whimpers go unheard and unanswered.

Erica Bradshaw, MD
Staff psychiatrist
Inpatient psychiatry
Houston Veterans Administration Medical Center
Houston, TX

I heartily agree with Dr. Henry Nasrallah’s stance about the treatment of chronically mentally ill individuals, specifically those with schizophrenia. I recently completed my psychiatry residency in Virginia. In addition to the consequences Dr. Nasrallah outlined in his editorial, I have identified a few additional disastrous effects of transferring care of severely mentally ill patients from state hospitals to the community service boards (CSBs).

Working in a hospital affiliated with a medical school meant that we took care of all indigent patients who were admitted. It is heartbreaking to spend weeks stabilizing a very ill patient and then send him or her back to the disastrous circumstances that often lead to the initial hospitalization. I saw patients discharged with appointments to CSBs that they had little chance of finding, getting to, or even remembering. These patients often were prescribed medications that I could not afford even with health insurance.

Discharged patients don’t fill prescriptions or they can’t remember medication schedules because they are too busy trying to survive. People who most need effective medicines have long ago become nonresponsive because of repeated periods of non-compliance.

Severely mentally ill persons do not have lobbyists in government; they are not likely to organize a march on Washington, DC. They have no voice, which is why their whimpers go unheard and unanswered.

Erica Bradshaw, MD
Staff psychiatrist
Inpatient psychiatry
Houston Veterans Administration Medical Center
Houston, TX

I read Dr. Henry Nasrallah’s editorial about the tragic consequences of deinstitutionalization (“Bring back the asylums?” From the Editor, Current Psychiatry, March 2008) with great enthusiasm.

Since 1981 I have devoted my career to treating chronic mentally ill individuals in community settings. For the past 6 years I have worked for a social service agency that provides on-site services to mentally ill tenants in permanent single-room occupancy housing. This agency serves approximately 1,500 tenants in several buildings. I have had intimate exposure to the experiences of individuals who a generation ago would have been placed in long-term institutions.

My private joke is that my agency runs the largest long-term psychiatric institution in New York state. However, over the past few years this no longer seems like a joke. Seeing the reality of these severely mentally ill persons’ lives—even in this protective setting of supervised housing run by an outstanding agency—is sobering and discouraging. What I see every day thoroughly supports and is living proof of the validity of Dr. Nasrallah’s editorial. It is a relief to have my thoughts validated because among community psychiatrists such thinking is viewed as heresy.

Alexis Brosen, MD
Clinical assistant professor of psychiatry
New York University School of Medicine
New York, NY

I read Dr. Henry Nasrallah’s editorial about the tragic consequences of deinstitutionalization (“Bring back the asylums?” From the Editor, Current Psychiatry, March 2008) with great enthusiasm.

Since 1981 I have devoted my career to treating chronic mentally ill individuals in community settings. For the past 6 years I have worked for a social service agency that provides on-site services to mentally ill tenants in permanent single-room occupancy housing. This agency serves approximately 1,500 tenants in several buildings. I have had intimate exposure to the experiences of individuals who a generation ago would have been placed in long-term institutions.

My private joke is that my agency runs the largest long-term psychiatric institution in New York state. However, over the past few years this no longer seems like a joke. Seeing the reality of these severely mentally ill persons’ lives—even in this protective setting of supervised housing run by an outstanding agency—is sobering and discouraging. What I see every day thoroughly supports and is living proof of the validity of Dr. Nasrallah’s editorial. It is a relief to have my thoughts validated because among community psychiatrists such thinking is viewed as heresy.

Alexis Brosen, MD
Clinical assistant professor of psychiatry
New York University School of Medicine
New York, NY

I read Dr. Henry Nasrallah’s editorial about the tragic consequences of deinstitutionalization (“Bring back the asylums?” From the Editor, Current Psychiatry, March 2008) with great enthusiasm.

Since 1981 I have devoted my career to treating chronic mentally ill individuals in community settings. For the past 6 years I have worked for a social service agency that provides on-site services to mentally ill tenants in permanent single-room occupancy housing. This agency serves approximately 1,500 tenants in several buildings. I have had intimate exposure to the experiences of individuals who a generation ago would have been placed in long-term institutions.

My private joke is that my agency runs the largest long-term psychiatric institution in New York state. However, over the past few years this no longer seems like a joke. Seeing the reality of these severely mentally ill persons’ lives—even in this protective setting of supervised housing run by an outstanding agency—is sobering and discouraging. What I see every day thoroughly supports and is living proof of the validity of Dr. Nasrallah’s editorial. It is a relief to have my thoughts validated because among community psychiatrists such thinking is viewed as heresy.

Alexis Brosen, MD
Clinical assistant professor of psychiatry
New York University School of Medicine
New York, NY

I enjoyed Dr. Henry Nasrallah’s editorial on sponsorless CME. The issue has polarized different groups, and I thought his ideas were sensible. We have to start looking for solutions instead of pointing fingers or avoiding accountability. Thanks for speaking up.

Second, Current Psychiatry is a favorite journal to me and a number of my colleagues. It is relevant and clinically focused yet has good evidence-based accountability. And to top it off, the articles can be mastered in a reasonably short period of time. I read more articles in Current Psychiatry than in any other journal, and I definitely am not alone in that practice.

John Battaglia, MD
Medical director
Program of Assertive Community Treatment
Clinical associate professor
Department of psychiatry
University of Wisconsin Medical School
Madison, WI

I enjoyed Dr. Henry Nasrallah’s editorial on sponsorless CME. The issue has polarized different groups, and I thought his ideas were sensible. We have to start looking for solutions instead of pointing fingers or avoiding accountability. Thanks for speaking up.

Second, Current Psychiatry is a favorite journal to me and a number of my colleagues. It is relevant and clinically focused yet has good evidence-based accountability. And to top it off, the articles can be mastered in a reasonably short period of time. I read more articles in Current Psychiatry than in any other journal, and I definitely am not alone in that practice.

John Battaglia, MD
Medical director
Program of Assertive Community Treatment
Clinical associate professor
Department of psychiatry
University of Wisconsin Medical School
Madison, WI

I enjoyed Dr. Henry Nasrallah’s editorial on sponsorless CME. The issue has polarized different groups, and I thought his ideas were sensible. We have to start looking for solutions instead of pointing fingers or avoiding accountability. Thanks for speaking up.

Second, Current Psychiatry is a favorite journal to me and a number of my colleagues. It is relevant and clinically focused yet has good evidence-based accountability. And to top it off, the articles can be mastered in a reasonably short period of time. I read more articles in Current Psychiatry than in any other journal, and I definitely am not alone in that practice.

John Battaglia, MD
Medical director
Program of Assertive Community Treatment
Clinical associate professor
Department of psychiatry
University of Wisconsin Medical School
Madison, WI

I applaud Dr. Henry Nasrallah’s forward thinking regarding encouraging creative new psychotropic drug development and supporting CME. CME programs—although vital for faculty and private practitioners—also are extremely valuable for residents, even though they don’t receive credit for completing the courses.

I would like to see your idea for a nonprofit, independent fund for CME activities take into account that all residency programs would need some support for CME and ensure that funding is equally distributed to programs large and small.

Jacqueline A. Hobbs, MD, PhD
Assistant professor
Departments of psychiatry and molecular genetics and microbiology
University of Florida College of Medicine
Gainesville, FL

I applaud Dr. Henry Nasrallah’s forward thinking regarding encouraging creative new psychotropic drug development and supporting CME. CME programs—although vital for faculty and private practitioners—also are extremely valuable for residents, even though they don’t receive credit for completing the courses.

I would like to see your idea for a nonprofit, independent fund for CME activities take into account that all residency programs would need some support for CME and ensure that funding is equally distributed to programs large and small.

Jacqueline A. Hobbs, MD, PhD
Assistant professor
Departments of psychiatry and molecular genetics and microbiology
University of Florida College of Medicine
Gainesville, FL

I applaud Dr. Henry Nasrallah’s forward thinking regarding encouraging creative new psychotropic drug development and supporting CME. CME programs—although vital for faculty and private practitioners—also are extremely valuable for residents, even though they don’t receive credit for completing the courses.

I would like to see your idea for a nonprofit, independent fund for CME activities take into account that all residency programs would need some support for CME and ensure that funding is equally distributed to programs large and small.

Jacqueline A. Hobbs, MD, PhD
Assistant professor
Departments of psychiatry and molecular genetics and microbiology
University of Florida College of Medicine
Gainesville, FL

While I agree with Dr. Henry Nasrallah that pharmaceutical companies’ policies need to be changed (“Breakthrough drugs and sponsorless CME: How the FDA can help,” From the Editor, Current Psychiatry, April 2008), I believe he overlooked the larger moral question and a potential intervention. Every dollar psychiatrists accept for personal use—no matter how free from bias— is one that could have been used to benefit our patients.

As physicians we need to set aside our deeply ingrained feelings of entitlement and assume responsibility for our education and sustenance. I can buy my own books, notepads, lunches, and even continuing medical education (CME). I cannot provide expanded patient assistance programs or lower medication costs. A pooled not-for-profit fund is an excellent idea; why not use it to buy generic medications for resident clinics to distribute free of charge or other patient-centered activities?

I recognize that funding CME without industry sponsorship would be difficult and would require fewer creature comforts and more funding from physicians. It likely will require creative use of Web-based teleconferencing, information sharing, or even streamed, prepackaged lectures from recognized experts. In the end, however, I believe a greater commitment to teaching each other and active learning will provide a greater benefit to ourselves and our patients.

Travis J. Fisher, MD
Medical College of Wisconsin
Milwaukee, WI

While I agree with Dr. Henry Nasrallah that pharmaceutical companies’ policies need to be changed (“Breakthrough drugs and sponsorless CME: How the FDA can help,” From the Editor, Current Psychiatry, April 2008), I believe he overlooked the larger moral question and a potential intervention. Every dollar psychiatrists accept for personal use—no matter how free from bias— is one that could have been used to benefit our patients.

As physicians we need to set aside our deeply ingrained feelings of entitlement and assume responsibility for our education and sustenance. I can buy my own books, notepads, lunches, and even continuing medical education (CME). I cannot provide expanded patient assistance programs or lower medication costs. A pooled not-for-profit fund is an excellent idea; why not use it to buy generic medications for resident clinics to distribute free of charge or other patient-centered activities?

I recognize that funding CME without industry sponsorship would be difficult and would require fewer creature comforts and more funding from physicians. It likely will require creative use of Web-based teleconferencing, information sharing, or even streamed, prepackaged lectures from recognized experts. In the end, however, I believe a greater commitment to teaching each other and active learning will provide a greater benefit to ourselves and our patients.

Travis J. Fisher, MD
Medical College of Wisconsin
Milwaukee, WI

While I agree with Dr. Henry Nasrallah that pharmaceutical companies’ policies need to be changed (“Breakthrough drugs and sponsorless CME: How the FDA can help,” From the Editor, Current Psychiatry, April 2008), I believe he overlooked the larger moral question and a potential intervention. Every dollar psychiatrists accept for personal use—no matter how free from bias— is one that could have been used to benefit our patients.

As physicians we need to set aside our deeply ingrained feelings of entitlement and assume responsibility for our education and sustenance. I can buy my own books, notepads, lunches, and even continuing medical education (CME). I cannot provide expanded patient assistance programs or lower medication costs. A pooled not-for-profit fund is an excellent idea; why not use it to buy generic medications for resident clinics to distribute free of charge or other patient-centered activities?

I recognize that funding CME without industry sponsorship would be difficult and would require fewer creature comforts and more funding from physicians. It likely will require creative use of Web-based teleconferencing, information sharing, or even streamed, prepackaged lectures from recognized experts. In the end, however, I believe a greater commitment to teaching each other and active learning will provide a greater benefit to ourselves and our patients.

Travis J. Fisher, MD
Medical College of Wisconsin
Milwaukee, WI

HISTORY: ‘They’re out to get me’

Mrs. V, age 64, tells her primary care physician she has felt “bad” for 2 weeks. She complains of depressed mood, middle insomnia, diminished appetite, poor concentration, and poor energy. She denies suicidal thoughts but reports feeling alone, overwhelmed, and unable to manage her daily life.

Mrs. V is very concerned about losing her job because she cannot function at work. She believes her coworkers may be plotting to get her fired. The primary care physician refers Mrs. V to us to evaluate her mood.

According to her daughter, Mrs. V has had multiple psychiatric hospitalizations; the most recent occurred 2 years ago when she was admitted for paranoia and disorganized behavior. The daughter also mentions that her mother has a remote history of daily alcohol use, drinking until she was intoxicated. Mrs. V says she occasionally drinks beer and she scores 2 out of 4 on the CAGE questionnaire, which may indicate alcohol dependence.

During mental status examination, Mrs. V is alert and oriented to person, place, and date. She is pleasant and cooperative but shows apparent thought blocking and some tangentiality. She has substantial difficulty answering questions and articulating symptoms. Speech is slow in rate and rhythm. Mrs. V’s mood is severely depressed and her affect constricted.

She denies suicidal or homicidal ideations or visual or auditory hallucinations. Cognitive testing reveals mild deficits in recall memory and poor concentration. Her insight is limited and her judgment fair.

Her medical history includes hypertension, hyperlipidemia, coronary artery disease, cardiac catheterization, and hyponatremia. Her medication regimen consists of aripiprazole, 15 mg/d; diltiazem, 180 mg/d; atenolol, 25 mg/d; aspirin, 325 mg/d; atorvastatin, 10 mg/d; sertraline, 50 mg/d; and ibuprofen, 600 mg as needed for hip pain. She also reports taking diuretics in the past.

Vital signs include blood pressure, 125/95 mm Hg; respirations, 16/min; temperature, 98.2° F; and pulse rate, 72/min. Serum investigations reveal sodium, 119 mEq/L (normal range: 135 to 145 mEq/L) and random blood sugar, 160 mg/dL (normal range: 60 to 114 mg/dL).

The authors’ observations

The combination of major depression with psychosis and hyponatremia makes Mrs. V’s case challenging. Hyponatremia in psychiatric inpatients can prompt medical consultation, thus possibly halting or delaying psychiatric treatment.

Hyponatremia has been associated with the use of:

• diuretics
  
• selective serotonin reuptake inhibitors (SSRIs)
  
• serotonin-norepinephrine reuptake inhibitors (SNRIs)
  
• tricyclic antidepressants
  
• calcium antagonists.
  

Among psychiatric inpatients, the risk of hyponatremia is doubled in women.¹ It is unclear, however, if female gender is an independent risk factor for hyponatremia. Sharabi et al² reported that patients of both sexes age >65 have a 9-fold greater risk of developing hyponatremia than younger counterparts.

In addition, hyponatremia risk during any antidepressant treatment is highest:

• in the summer
  
• during the first weeks of treatment
  
• with concomitant drug use, especially with diuretics.³
  

The authors’ observations

Based on Mrs. V’s initial lab results (Table 1), we classify her hyponatremia as euvolemic, with high urine osmolarity (≥100 mOsm/L). That helps narrow our differential diagnosis to glucocorticoid deficiency, hypothyroidism, and SIADH (Table 2).⁵ We exclude psychogenic polydipsia, “tea and toast” syndrome, or beer potomania because they usually present as euvolemic hyponatremia with low urinary osmolality.

SSRI use in elderly persons has been associated with hyponatremia, which in some cases may be consistent with SIADH. Unfortunately, few psychiatrists are aware of this potentially fatal side effect.

SIADH occurs in association with reduced serum osmolality. It is characterized by:

• hypotonic hyponatremia (serum sodium
• inappropriately elevated urine osmolarity (>200 mOsm/L) relative to plasma osmolarity
  
• elevated urine sodium (typically >20 mEq/L).⁴
  

The key to the pathophysiology, signs, symptoms, and treatment of SIADH is understanding that the hyponatremia is a result of excess water and not a sodium deficiency. Hyponatremia’s signs and symptoms primarily are related to CNS dysfunction and correlate with how rapidly and severely the condition develops.

We monitor Mrs. V for anorexia, nausea, and malaise because they would be the earliest findings, followed by headache, irritability, confusion, muscle cramps, weakness, obtundation, seizures, and coma. These occur as osmotic fluid shifts and results in cerebral edema and increased intracranial pressure. When sodium concentration drops below 105 mEq/L, life-threatening complications are likely.

Table 1

Mrs. V’s laboratory results

Mrs. V’s laboratory results

SSRIs and SIADH

Bouman et al⁶ estimated that the incidence of SSRI-induced SIADH in elderly patients is 12%. Liu et al⁷ described 706 cases of hyponatremia associated with SSRI use in unpublished reports. Fluoxetine was most commonly the cause (75.3% cases), followed by paroxetine (12.4%), sertraline (11.7%), and fluvoxamine (1.5%). Resuming the same drug resulted in hyponatremia in 16 of 24 of these cases (66.7%).

Kirby et al,⁸ however, found no clear advantages in different SSRIs’ propensity to cause hyponatremia. Seventy-one percent of patients treated with the SNRI venlafaxine developed hyponatremia, compared with 32% taking paroxetine and 29% receiving sertraline. It is unclear whether a specific SSRI or venlafaxine has a stronger association with hyponatremia than any other antidepressant.

Hyponatremia’s nonspecific symptoms and wide range of time to detection (1 to 253 days) suggest clinicians usually detect the condition by chance rather than specifically assessing for it.⁹

TREATMENT: Medication change?

Coordinating Mrs. V’s depression and hyponatremia treatment is critical. We propose discontinuing sertraline and treating Mrs. V’s symptoms with electroconvulsive therapy (ECT). She refuses ECT, stating “I don’t feel that bad. My father was treated with ECT and I am scared of it.”

The authors’ observations

SSRI-induced hyponatremia can be transient or persistent and recurrent. The usual approach is to discontinue the SSRI and try a different antidepressant. Because hyponatremia has been associated with all SSRIs and SNRIs, it would be prudent to choose an alternate antidepressant agent outside these classes. If patients must continue taking an antidepressant that causes hyponatremia, avoid concurrent use of drugs that cause hyponatremia, restrict fluid intake, and consider adding a medication that prevents hyponatremia, such as demeclocycline or fludrocortisone.

SSRI-induced hyponatremia may resolve:

• with SSRI discontinuation alone¹¹
  
• with fluid restriction and without discontinuation of the SSRI¹¹
  
• with drug discontinuation, fluid restriction, and sodium chloride and potassium supplementation.¹²
  

FOLLOW-UP: Analysis error?

Despite modifications to Mrs. V’s diet, her fasting serum glucose level remains >100. She is diagnosed with diabetes mellitus type 2 and treated with metformin. We continue mirtazapine, which has successfully controlled Mrs. V’s depressive symptoms. Her serum sodium levels start normalizing.

The authors’ observations

Related resources

• Siegel AJ. Hyponatremia in psychiatric patients: update on evaluation and management. Harv Rev Psychiatry 2008;16(1):13-24.
  
• Atalay A, Turhan N, Aki OE. A challenging case of syndrome of inappropriate secretion of antidiuretic hormone in an elderly patient secondary to quetiapine. South Med J 2007;100(8):832-3.
  

• Aripiprazole • Abilify
  
• Atenolol • Tenormin
  
• Atorvastatin • Lipitor
  
• Demeclocycline • Declomycin, Declostatin, others
  
• Diltiazem • Cardizem, Dilacor, others
  
• Fludrocortisone • Florinef
  
• Fluvoxamine • Luvox
  
• Ibuprofen • Advil, Motrin, others
  
• Metformin • Glucophage, Diabex, others
  
• Mirtazapine • Remeron
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Dr. Romanowicz reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.

Dr. Wilson receives research support from the National Institute of Mental Health, the Veterans Administration, the State of Nebraska, Health Futures Foundation, Inc., AstraZeneca, Dainippon Sumitomo Pharma, Eli Lilly and Company, and Pfizer Inc. and serves as a consultant to the Substance Abuse and Mental Health Services Administration and the State of Nebraska.

HISTORY: ‘They’re out to get me’

Mrs. V, age 64, tells her primary care physician she has felt “bad” for 2 weeks. She complains of depressed mood, middle insomnia, diminished appetite, poor concentration, and poor energy. She denies suicidal thoughts but reports feeling alone, overwhelmed, and unable to manage her daily life.

Mrs. V is very concerned about losing her job because she cannot function at work. She believes her coworkers may be plotting to get her fired. The primary care physician refers Mrs. V to us to evaluate her mood.

According to her daughter, Mrs. V has had multiple psychiatric hospitalizations; the most recent occurred 2 years ago when she was admitted for paranoia and disorganized behavior. The daughter also mentions that her mother has a remote history of daily alcohol use, drinking until she was intoxicated. Mrs. V says she occasionally drinks beer and she scores 2 out of 4 on the CAGE questionnaire, which may indicate alcohol dependence.

During mental status examination, Mrs. V is alert and oriented to person, place, and date. She is pleasant and cooperative but shows apparent thought blocking and some tangentiality. She has substantial difficulty answering questions and articulating symptoms. Speech is slow in rate and rhythm. Mrs. V’s mood is severely depressed and her affect constricted.

She denies suicidal or homicidal ideations or visual or auditory hallucinations. Cognitive testing reveals mild deficits in recall memory and poor concentration. Her insight is limited and her judgment fair.

Her medical history includes hypertension, hyperlipidemia, coronary artery disease, cardiac catheterization, and hyponatremia. Her medication regimen consists of aripiprazole, 15 mg/d; diltiazem, 180 mg/d; atenolol, 25 mg/d; aspirin, 325 mg/d; atorvastatin, 10 mg/d; sertraline, 50 mg/d; and ibuprofen, 600 mg as needed for hip pain. She also reports taking diuretics in the past.

Vital signs include blood pressure, 125/95 mm Hg; respirations, 16/min; temperature, 98.2° F; and pulse rate, 72/min. Serum investigations reveal sodium, 119 mEq/L (normal range: 135 to 145 mEq/L) and random blood sugar, 160 mg/dL (normal range: 60 to 114 mg/dL).

The authors’ observations

The combination of major depression with psychosis and hyponatremia makes Mrs. V’s case challenging. Hyponatremia in psychiatric inpatients can prompt medical consultation, thus possibly halting or delaying psychiatric treatment.

Hyponatremia has been associated with the use of:

• diuretics
  
• selective serotonin reuptake inhibitors (SSRIs)
  
• serotonin-norepinephrine reuptake inhibitors (SNRIs)
  
• tricyclic antidepressants
  
• calcium antagonists.
  

Among psychiatric inpatients, the risk of hyponatremia is doubled in women.¹ It is unclear, however, if female gender is an independent risk factor for hyponatremia. Sharabi et al² reported that patients of both sexes age >65 have a 9-fold greater risk of developing hyponatremia than younger counterparts.

In addition, hyponatremia risk during any antidepressant treatment is highest:

• in the summer
  
• during the first weeks of treatment
  
• with concomitant drug use, especially with diuretics.³
  

The authors’ observations

Based on Mrs. V’s initial lab results (Table 1), we classify her hyponatremia as euvolemic, with high urine osmolarity (≥100 mOsm/L). That helps narrow our differential diagnosis to glucocorticoid deficiency, hypothyroidism, and SIADH (Table 2).⁵ We exclude psychogenic polydipsia, “tea and toast” syndrome, or beer potomania because they usually present as euvolemic hyponatremia with low urinary osmolality.

SSRI use in elderly persons has been associated with hyponatremia, which in some cases may be consistent with SIADH. Unfortunately, few psychiatrists are aware of this potentially fatal side effect.

SIADH occurs in association with reduced serum osmolality. It is characterized by:

• hypotonic hyponatremia (serum sodium
• inappropriately elevated urine osmolarity (>200 mOsm/L) relative to plasma osmolarity
  
• elevated urine sodium (typically >20 mEq/L).⁴
  

The key to the pathophysiology, signs, symptoms, and treatment of SIADH is understanding that the hyponatremia is a result of excess water and not a sodium deficiency. Hyponatremia’s signs and symptoms primarily are related to CNS dysfunction and correlate with how rapidly and severely the condition develops.

We monitor Mrs. V for anorexia, nausea, and malaise because they would be the earliest findings, followed by headache, irritability, confusion, muscle cramps, weakness, obtundation, seizures, and coma. These occur as osmotic fluid shifts and results in cerebral edema and increased intracranial pressure. When sodium concentration drops below 105 mEq/L, life-threatening complications are likely.

Table 1

Mrs. V’s laboratory results

Mrs. V’s laboratory results

SSRIs and SIADH

Bouman et al⁶ estimated that the incidence of SSRI-induced SIADH in elderly patients is 12%. Liu et al⁷ described 706 cases of hyponatremia associated with SSRI use in unpublished reports. Fluoxetine was most commonly the cause (75.3% cases), followed by paroxetine (12.4%), sertraline (11.7%), and fluvoxamine (1.5%). Resuming the same drug resulted in hyponatremia in 16 of 24 of these cases (66.7%).

Kirby et al,⁸ however, found no clear advantages in different SSRIs’ propensity to cause hyponatremia. Seventy-one percent of patients treated with the SNRI venlafaxine developed hyponatremia, compared with 32% taking paroxetine and 29% receiving sertraline. It is unclear whether a specific SSRI or venlafaxine has a stronger association with hyponatremia than any other antidepressant.

Hyponatremia’s nonspecific symptoms and wide range of time to detection (1 to 253 days) suggest clinicians usually detect the condition by chance rather than specifically assessing for it.⁹

TREATMENT: Medication change?

Coordinating Mrs. V’s depression and hyponatremia treatment is critical. We propose discontinuing sertraline and treating Mrs. V’s symptoms with electroconvulsive therapy (ECT). She refuses ECT, stating “I don’t feel that bad. My father was treated with ECT and I am scared of it.”

The authors’ observations

SSRI-induced hyponatremia can be transient or persistent and recurrent. The usual approach is to discontinue the SSRI and try a different antidepressant. Because hyponatremia has been associated with all SSRIs and SNRIs, it would be prudent to choose an alternate antidepressant agent outside these classes. If patients must continue taking an antidepressant that causes hyponatremia, avoid concurrent use of drugs that cause hyponatremia, restrict fluid intake, and consider adding a medication that prevents hyponatremia, such as demeclocycline or fludrocortisone.

SSRI-induced hyponatremia may resolve:

• with SSRI discontinuation alone¹¹
  
• with fluid restriction and without discontinuation of the SSRI¹¹
  
• with drug discontinuation, fluid restriction, and sodium chloride and potassium supplementation.¹²
  

FOLLOW-UP: Analysis error?

Despite modifications to Mrs. V’s diet, her fasting serum glucose level remains >100. She is diagnosed with diabetes mellitus type 2 and treated with metformin. We continue mirtazapine, which has successfully controlled Mrs. V’s depressive symptoms. Her serum sodium levels start normalizing.

The authors’ observations

Related resources

• Siegel AJ. Hyponatremia in psychiatric patients: update on evaluation and management. Harv Rev Psychiatry 2008;16(1):13-24.
  
• Atalay A, Turhan N, Aki OE. A challenging case of syndrome of inappropriate secretion of antidiuretic hormone in an elderly patient secondary to quetiapine. South Med J 2007;100(8):832-3.
  

• Aripiprazole • Abilify
  
• Atenolol • Tenormin
  
• Atorvastatin • Lipitor
  
• Demeclocycline • Declomycin, Declostatin, others
  
• Diltiazem • Cardizem, Dilacor, others
  
• Fludrocortisone • Florinef
  
• Fluvoxamine • Luvox
  
• Ibuprofen • Advil, Motrin, others
  
• Metformin • Glucophage, Diabex, others
  
• Mirtazapine • Remeron
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Dr. Romanowicz reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.

Dr. Wilson receives research support from the National Institute of Mental Health, the Veterans Administration, the State of Nebraska, Health Futures Foundation, Inc., AstraZeneca, Dainippon Sumitomo Pharma, Eli Lilly and Company, and Pfizer Inc. and serves as a consultant to the Substance Abuse and Mental Health Services Administration and the State of Nebraska.

HISTORY: ‘They’re out to get me’

Mrs. V, age 64, tells her primary care physician she has felt “bad” for 2 weeks. She complains of depressed mood, middle insomnia, diminished appetite, poor concentration, and poor energy. She denies suicidal thoughts but reports feeling alone, overwhelmed, and unable to manage her daily life.

Mrs. V is very concerned about losing her job because she cannot function at work. She believes her coworkers may be plotting to get her fired. The primary care physician refers Mrs. V to us to evaluate her mood.

According to her daughter, Mrs. V has had multiple psychiatric hospitalizations; the most recent occurred 2 years ago when she was admitted for paranoia and disorganized behavior. The daughter also mentions that her mother has a remote history of daily alcohol use, drinking until she was intoxicated. Mrs. V says she occasionally drinks beer and she scores 2 out of 4 on the CAGE questionnaire, which may indicate alcohol dependence.

During mental status examination, Mrs. V is alert and oriented to person, place, and date. She is pleasant and cooperative but shows apparent thought blocking and some tangentiality. She has substantial difficulty answering questions and articulating symptoms. Speech is slow in rate and rhythm. Mrs. V’s mood is severely depressed and her affect constricted.

She denies suicidal or homicidal ideations or visual or auditory hallucinations. Cognitive testing reveals mild deficits in recall memory and poor concentration. Her insight is limited and her judgment fair.

Her medical history includes hypertension, hyperlipidemia, coronary artery disease, cardiac catheterization, and hyponatremia. Her medication regimen consists of aripiprazole, 15 mg/d; diltiazem, 180 mg/d; atenolol, 25 mg/d; aspirin, 325 mg/d; atorvastatin, 10 mg/d; sertraline, 50 mg/d; and ibuprofen, 600 mg as needed for hip pain. She also reports taking diuretics in the past.

Vital signs include blood pressure, 125/95 mm Hg; respirations, 16/min; temperature, 98.2° F; and pulse rate, 72/min. Serum investigations reveal sodium, 119 mEq/L (normal range: 135 to 145 mEq/L) and random blood sugar, 160 mg/dL (normal range: 60 to 114 mg/dL).

The authors’ observations

The combination of major depression with psychosis and hyponatremia makes Mrs. V’s case challenging. Hyponatremia in psychiatric inpatients can prompt medical consultation, thus possibly halting or delaying psychiatric treatment.

Hyponatremia has been associated with the use of:

• diuretics
  
• selective serotonin reuptake inhibitors (SSRIs)
  
• serotonin-norepinephrine reuptake inhibitors (SNRIs)
  
• tricyclic antidepressants
  
• calcium antagonists.
  

Among psychiatric inpatients, the risk of hyponatremia is doubled in women.¹ It is unclear, however, if female gender is an independent risk factor for hyponatremia. Sharabi et al² reported that patients of both sexes age >65 have a 9-fold greater risk of developing hyponatremia than younger counterparts.

In addition, hyponatremia risk during any antidepressant treatment is highest:

• in the summer
  
• during the first weeks of treatment
  
• with concomitant drug use, especially with diuretics.³
  

The authors’ observations

Based on Mrs. V’s initial lab results (Table 1), we classify her hyponatremia as euvolemic, with high urine osmolarity (≥100 mOsm/L). That helps narrow our differential diagnosis to glucocorticoid deficiency, hypothyroidism, and SIADH (Table 2).⁵ We exclude psychogenic polydipsia, “tea and toast” syndrome, or beer potomania because they usually present as euvolemic hyponatremia with low urinary osmolality.

SSRI use in elderly persons has been associated with hyponatremia, which in some cases may be consistent with SIADH. Unfortunately, few psychiatrists are aware of this potentially fatal side effect.

SIADH occurs in association with reduced serum osmolality. It is characterized by:

• hypotonic hyponatremia (serum sodium
• inappropriately elevated urine osmolarity (>200 mOsm/L) relative to plasma osmolarity
  
• elevated urine sodium (typically >20 mEq/L).⁴
  

The key to the pathophysiology, signs, symptoms, and treatment of SIADH is understanding that the hyponatremia is a result of excess water and not a sodium deficiency. Hyponatremia’s signs and symptoms primarily are related to CNS dysfunction and correlate with how rapidly and severely the condition develops.

We monitor Mrs. V for anorexia, nausea, and malaise because they would be the earliest findings, followed by headache, irritability, confusion, muscle cramps, weakness, obtundation, seizures, and coma. These occur as osmotic fluid shifts and results in cerebral edema and increased intracranial pressure. When sodium concentration drops below 105 mEq/L, life-threatening complications are likely.

Table 1

Mrs. V’s laboratory results

Mrs. V’s laboratory results

SSRIs and SIADH

Bouman et al⁶ estimated that the incidence of SSRI-induced SIADH in elderly patients is 12%. Liu et al⁷ described 706 cases of hyponatremia associated with SSRI use in unpublished reports. Fluoxetine was most commonly the cause (75.3% cases), followed by paroxetine (12.4%), sertraline (11.7%), and fluvoxamine (1.5%). Resuming the same drug resulted in hyponatremia in 16 of 24 of these cases (66.7%).

Kirby et al,⁸ however, found no clear advantages in different SSRIs’ propensity to cause hyponatremia. Seventy-one percent of patients treated with the SNRI venlafaxine developed hyponatremia, compared with 32% taking paroxetine and 29% receiving sertraline. It is unclear whether a specific SSRI or venlafaxine has a stronger association with hyponatremia than any other antidepressant.

Hyponatremia’s nonspecific symptoms and wide range of time to detection (1 to 253 days) suggest clinicians usually detect the condition by chance rather than specifically assessing for it.⁹

TREATMENT: Medication change?

Coordinating Mrs. V’s depression and hyponatremia treatment is critical. We propose discontinuing sertraline and treating Mrs. V’s symptoms with electroconvulsive therapy (ECT). She refuses ECT, stating “I don’t feel that bad. My father was treated with ECT and I am scared of it.”

The authors’ observations

SSRI-induced hyponatremia can be transient or persistent and recurrent. The usual approach is to discontinue the SSRI and try a different antidepressant. Because hyponatremia has been associated with all SSRIs and SNRIs, it would be prudent to choose an alternate antidepressant agent outside these classes. If patients must continue taking an antidepressant that causes hyponatremia, avoid concurrent use of drugs that cause hyponatremia, restrict fluid intake, and consider adding a medication that prevents hyponatremia, such as demeclocycline or fludrocortisone.

SSRI-induced hyponatremia may resolve:

• with SSRI discontinuation alone¹¹
  
• with fluid restriction and without discontinuation of the SSRI¹¹
  
• with drug discontinuation, fluid restriction, and sodium chloride and potassium supplementation.¹²
  

FOLLOW-UP: Analysis error?

Despite modifications to Mrs. V’s diet, her fasting serum glucose level remains >100. She is diagnosed with diabetes mellitus type 2 and treated with metformin. We continue mirtazapine, which has successfully controlled Mrs. V’s depressive symptoms. Her serum sodium levels start normalizing.

The authors’ observations

Related resources

• Siegel AJ. Hyponatremia in psychiatric patients: update on evaluation and management. Harv Rev Psychiatry 2008;16(1):13-24.
  
• Atalay A, Turhan N, Aki OE. A challenging case of syndrome of inappropriate secretion of antidiuretic hormone in an elderly patient secondary to quetiapine. South Med J 2007;100(8):832-3.
  

• Aripiprazole • Abilify
  
• Atenolol • Tenormin
  
• Atorvastatin • Lipitor
  
• Demeclocycline • Declomycin, Declostatin, others
  
• Diltiazem • Cardizem, Dilacor, others
  
• Fludrocortisone • Florinef
  
• Fluvoxamine • Luvox
  
• Ibuprofen • Advil, Motrin, others
  
• Metformin • Glucophage, Diabex, others
  
• Mirtazapine • Remeron
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Dr. Romanowicz reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.

Dr. Wilson receives research support from the National Institute of Mental Health, the Veterans Administration, the State of Nebraska, Health Futures Foundation, Inc., AstraZeneca, Dainippon Sumitomo Pharma, Eli Lilly and Company, and Pfizer Inc. and serves as a consultant to the Substance Abuse and Mental Health Services Administration and the State of Nebraska.

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.

Diagnosed 7 years ago with Alzheimer’s disease (AD), Mrs. B, age 82, resides in an assisted living facility whose staff is trained to care for older persons with dementia. Over the past 2 months she has shown an escalating pattern of psychosis and aggression, despite one-to-one attention and verbal reassurance.

At first Mrs. B’s psychosis was restricted to occasional rape accusations during assisted bathing and aggression manifested by banging her hand repetitively on furniture, causing skin tears. In the last week, she has been accusing staff and patients of stealing her belongings and has assaulted a staff member and another resident. When supervisors at the facility advise Mrs. B’s husband that she can no longer stay there, he takes her to a local emergency room, from which she is admitted involuntarily to a geriatric psychiatry inpatient unit.

For many patients and families, the most problematic aspects of dementia are neuropsychiatric symptoms—depression, sleep disturbance, psychosis, and aggression. Psychosis affects approximately 40% of persons with AD, whereas ≥80% of persons with dementia experience agitation at some point in the illness.¹ These symptoms can lead to:

• caregiver morbidity
• poor patient quality of life
• early patient institutionalization.²

Although no drug has been FDA-approved for treating dementia’s neuropsychiatric symptoms, psychiatrists often use off-label psychotropics—especially antipsychotics—to ameliorate them. This practice is controversial because of public perception that antipsychotics are used in dementia patients to create “zombies” to lighten healthcare workers’ burden. Nonetheless, because dementia patients with psychosis and severe agitation/aggression can pose risks to themselves and those around them, efforts to treat these symptoms are warranted.

Box

The FDA’s “black-box” warnings about using atypical agents in patients with dementia add another layer of complexity to your treatment decisions (Box).^3,4 The public is well served by evidence identifying risks associated with prescription medications, but the FDA data do little to help millions of families answer the question, “And so, what now?”

Recognizing that solid empiric evidence is lacking, we attempt to address this lingering question for clinicians, patients, and caregivers who must deal with these symptoms while science tries to provide a more definitive answer.

5-step evaluation

A 5-step initial evaluation of persons with dementia who present with psychosis and/or agitation/aggression includes establishing the frequency, severity, and cause of these symptoms as well as the effectiveness of past treatments and strategies (Algorithm).⁵

Because adverse drug effects are a potentially reversible cause of psychosis and agitation, review the patient’s drug list—including “as needed” medications—from records at a facility or from family report. Mrs. B’s record from the assisted living facility reveals she was receiving:

• atenolol, 25 mg/d
• aspirin, 81 mg/d
• extended-release oxybutynin, 10 mg at bedtime
• psyllium, one packet daily
• hydrocodone/acetaminophen, 5/500 mg every 4 hours as needed for pain
• lorazepam, 1 mg every 6 hours as needed for agitation
• diphenhydramine, 25 mg at bedtime
• paroxetine, 20 mg/d
• haloperidol, 5 mg at bedtime
• memantine, 10 mg twice a day.

Mrs. B’s medication list is revealing for reasons that, unfortunately, are not rare. She is receiving 3 anticholinergic medications—oxybutynin, diphenhydramine, and paroxetine—that may be worsening her mental status and behavior directly through CNS effects, possibly in combination with frequent benzodiazepine use.

Anticholinergics also can lead to behavior changes via peripheral side effects. Constipation and urinary retention may cause discomfort that an aphasic patient “acts out.” A patient may be experiencing pain related to these side effects and receiving opioid analgesics, which can worsen constipation and urinary retention. Uncontrolled pain related to musculoskeletal disease or neuropathy may merit treatment that will reduce behavioral disturbances.

Mrs. B also was being catheterized every 8 hours as needed for urinary retention. The invasive and unpleasant nature of urinary catheterization is likely to worsen behavior and increases the risk of one of the most common “asymptomatic” etiologies of behavioral symptoms in dementia—urinary tract infection (UTI).

Algorithm

5-step evaluation of dementia patients
with psychosis and/or agitation/aggression*

CASE CONTINUED: Persistent agitation

After evaluating Mrs. B, the psychiatrist limits her medications to atenolol, aspirin, psyllium, and memantine, and begins to taper lorazepam and paroxetine. Laboratory, radiologic, and physical examinations reveal UTI, fecal impaction, bladder distension, and mild hyponatremia. She is given a phosphosoda enema and ciprofloxacin, 250 mg/d for 5 days.

Despite one-to-one nursing care, frequent reorientation, and attempts to interest her in art therapy, Mrs. B remains agitated and postures to strike staff members and other patients. She denies pain or discomfort. Fearing that someone might be injured, the nurse pages the on-duty psychiatrist.

The nurse then calls Mr. B, who has durable power of attorney for his wife’s healthcare. When the nurse advises Mr. B that the psychiatrist has ordered risperidone, 0.5 mg, he immediately interjects that the psychiatrist at the assisted living facility told him haloperidol should be used for his wife’s symptoms because other antipsychotics can cause strokes and death.

Typical vs atypical antipsychotics

Mrs. B’s nurse may have to delay administering risperidone while she puts Mr. B in contact with the psychiatrist. In an emergent situation when well-trained staff have assessed for common reversible causes of agitation and tried reasonable nonpharmacologic means to calm the patient, few people would argue against using medication to preserve the safety of the patient and others. To avoid questions such as this during a crisis, obtain informed consent at admission from the patient or (more likely) the proxy decision-maker for medications you anticipate the patient might receive during hospitalization.

The larger question is whether typical antipsychotics are preferred for dementia-related psychosis and agitation/aggression because the FDA has not issued the same global black-box warning for this class. Astute clinicians realize that a lack of evidence of harm is not evidence of a lack of harm. In fact, since the black-box warnings for atypical antipsychotics in dementia emerged, several studies have examined whether the same risks exist for typical agents.

Evidence regarding risk of stroke and death with the use of typical and atypical antipsychotics in patients with dementia is summarized in Table 1.^6-13 Most evidence, including numerous studies in the past year, comes from retrospective database analyses. Prospective head-to-head comparisons of atypical and typical antipsychotics in dementia are scarce, and future prospective comparisons would be unethical.

No evidence suggests that typical antipsychotics mitigate the risks of stroke or death in dementia compared with atypical agents. Moreover, typical agents are more likely than atypicals to cause movement-related side effects—especially tardive dyskinesia and parkinsonism—in older adults with dementia.¹⁴

Table 1

Typical antipsychotics: Safer than atypicals for older patients?

CASE CONTINUED: Moderate relief from risperidone

After the psychiatrist explains the data on atypical vs typical antipsychotics in dementia—and the lack of FDA-approved treatments—Mr. B consents to the use of risperidone. He believes his wife would have wanted to try a medication with a moderate chance of relieving her internal distress and preventing her from harming anyone.

Risperidone provides moderate relief of Mrs. B’s aggression and paranoia. The next day Mr. B visits the unit and asks to speak with the psychiatrist. Although he appreciates the staff’s caring attitude, he says, “There must be safer or better ways to deal with these symptoms than medications like risperidone. I just don’t want the guilt of causing my wife to have a stroke or pass away.” He also asks, “How long will she have to take this medication?”

Evidence for efficacy

In addition to discussing antipsychotics’ risk in dementia, we also need to highlight their efficacy and effectiveness. A recent meta-analysis of 15 randomized controlled trials of atypical antipsychotics for agitation and/or psychosis in dementia included studies with risperidone, olanzapine, aripiprazole, and quetiapine.³ Most study participants were institutionalized, female, and had AD.

Psychosis scores improved in pooled studies of risperidone, whereas global neuropsychiatric disturbance improved with risperidone and aripiprazole. Effects were more notable in:

• persons without psychosis
• those living in nursing homes
• patients with severe cognitive impairment.

Subsequent placebo-controlled trials of risperidone, quetiapine, and aripiprazole—most focusing on patients with AD—reveal that atypical and typical antipsychotics have modest efficacy in reducing aggression and psychosis.^15-19 However, to some extent the National Institute of Mental Health Clinical Antipsychotic Trial of Intervention Effectiveness Study for Alzheimer’s Disease (CATIE-AD)—the largest nonindustry-funded study conducted to address this question—called this conclusion into question.²⁰ Risperidone and olanzapine (but not quetiapine) were efficacious in that fewer patients taking them vs placebo dropped out because of lack of efficacy. Antipsychotics were not effective overall, however, because the primary outcome—all-cause discontinuation rate—was similar for all 3 drugs and placebo. This indicates that on average these medications’ side effect burden may offset their efficacy, though individual patients’ responses may vary.

Alternatives to antipsychotics

Mr. B also raised the issue of treatment alternatives, such as no treatment, other psychotropics (Table 2),^5,21 and nonpharmacologic methods (Table 3).²²

“No treatment” does not imply a lack of assessment or intervention. Always examine patients for iatrogenic, medical, psychosocial, or other precipitants of behavioral symptoms. No treatment may be viable in mild to moderate cases but is impractical for patients with severe psychosis or agitation. Untreated, these symptoms could compromise safety or leave the patient without housing options.

Although possibly underused because of time constraints, reimbursement issues, or lack of training, nonpharmacologic strategies to treat aggression and psychosis in dementia are appealing alternatives to antipsychotics. Little empiric evidence supports nonpharmacologic strategies, however.²²

Treatment decisions need to consider patients’ and caregivers’ value systems. Proxy decision-makers should examine treatment decisions in terms of how they believe the patient would view the alternatives. Without a specific advance directive, however, even well-intentioned decision-makers are likely to “contaminate” decisions with their own values and interests.

After discussing with the decision-maker various treatments’ risks and benefits, it might be useful to ask, for example, “If Mrs. B could have foreseen her behaviors 10 years ago, what do you think she would have wanted us to do? Some people might have been mortified by the thought of attacking other people, whereas other people would not mind this as much as the fear of being ‘overmedicated.’ Which end of the spectrum do you think she would have leaned toward?”

When medical research does not offer clear answers for the “right” next clinical step, clinicians can:

• acknowledge our own limits and those of human knowledge
• engage the caregiver (or, when appropriate, the patient) in shared decision-making, recognizing that some people will appreciate the opportunity for “equal partnership” whereas others will want us to decide based on our best clinical judgment.

Table 2

Pharmacologic alternatives to antipsychotics: What the evidence says

Table 3

How well do psychosocial/behavioral therapies manage
psychosis/agitation in dementia?*

Duration of treatment

Limited evidence leaves psychiatrists largely on our own in regards to how long to continue pharmacotherapy with antipsychotics. Neuropsychiatric symptoms such as psychosis and agitation exhibit variable patterns. Symptoms may wax and wane for unclear reasons.

Given the tenuous nature of the risk-benefit profile for atypical antipsychotics in dementia, consider a gradual taper for persons with dementia who remain asymptomatic after 3 to 6 months of atypical antipsychotic treatment. Monitor them closely for symptom recurrence.⁵

Carefully consider the necessary duration of antipsychotic therapy in patients (such as Mrs. B) in whom you can identify possibly reversible precipitants of psychosis and aggression. Patients may have a delayed beneficial response to the correction of precipitating factors such as medical illness, physical discomfort, or medication side effects.

Mrs. B received risperidone, but evidence for efficacy and safety in dementia-related psychosis or agitation does not yet significantly distinguish among the atypical agents (except that data are limited for ziprasidone and clozapine). Usual starting and target doses are provided in Table 4.²³

Table 4

Atypicals in dementia: Starting and target doses

Related resources

• Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957-70.
• American Association for Geriatric Psychiatry position statement: principles of care for persons with dementia resulting from Alzheimer disease. www.aagponline.org/prof/position_caredmnalz.asp.

Drug brand names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Buspirone • Buspar
• Carbamazepine • Tegretol
• Ciprofloxacin • Ciloxan
• Citalopram • Celexa
• Clozapine • Clozaril
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Donepezil • Aricept
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Lortab, Vicodin
• Lorazepam • Ativan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxybutynin • Ditropan
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Sertraline • Zoloft
• Trazodone • Desyrel
• Ziprasidone • Geodon

Disclosure

Dr. Meeks receives research/grant support from the John A. Hartford Foundation, the Mental Health Research Foundation, NARSAD, and the U.S. Department of Health and Human Services’ Health Resources and Services Administration.

Dr. Jeste receives research/grant support from the John A. Hartford Foundation, the National Institute of Aging, and the National Institute of Mental Health. AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Janssen, L.P. provide free medications for an NIMH-funded study for which Dr. Jeste is the principal investigator.