Ms. J started losing weight deliberately at age 14 while attending boarding school. She lost 25 lbs by jogging 6 miles per day, exercising another 2 hours, avoiding meat, abusing laxatives, and drinking large quantities of coffee.

She was referred to a school counselor because of her weight loss and returned home. She was happier at a local high school and recovered to normal weight. In college, however, she reverted to compulsive exercising and preoccupation with her weight after the break-up of her first intimate relationship.

Now at age 22, Ms. J has persistently failed to gain weight during outpatient therapy for anorexia nervosa. At 5′7″ she weighs 98 lbs. On the day she was to be hospitalized involuntarily, she took 25 diphenhydramine tablets, which her psychiatrist viewed as a suicide threat. The overdose was treated in the emergency room with ipecac syrup, and she was admitted for inpatient eating disorder treatment.

Like Ms. J, patients with anorexia nervosa resist treatment and deny having most diagnostic signs and symptoms. Based on the evidence and my 30 years of treating anorectic patients,¹ this article offers suggestions to help you:

• gather accurate histories from patients and their families
• identify common psychiatric comorbidities
• gain the patient’s trust during treatment
• provide effective dual therapy, with cognitive-behavioral and pharmacologic components.

Table 1

Diagnostic criteria for anorexia nervosa

Making the diagnosis

Anorexia nervosa is characterized by underweight, fear of gaining weight, disturbed body concept, and amenorrhea (Table 1). Its core psychological symptoms have been described as:

• relentless pursuit of thinness
• denial of cachexia
• and feelings of general ineffectiveness.²

The patient may say she feels fat even though emaciated or that parts of her body are too large. This disturbed experience of body weight or shape may represent sublimation and displacement for feelings of inadequacy. Because anorectic patients stay thin so effectively, they may feel a sense of accomplishment by evaluating themselves in terms of their thinness. Cognitive therapy focuses on correcting patients’ pervasive sense of inadequacy, as manifest in maturity fears and lack of confidence in coping with life’s problems.³

Subtypes. Anorexia nervosa has two subtypes—restricting and binge eating/purging—that differ in behavioral and medical symptoms.⁴ Patients with binge eating/purging show:

• higher rates of impulsivity (suicide attempts, self-mutilation, stealing, and alcohol and other substance abuse)
• more-prevalent impulsive personality disorders (borderline personality disorder, hysterical personality disorder)
• medical problems caused by purging.

Restricting-type patients are often dependent and submissive, with difficulty separating from parents. These patients may be preoccupied with orderliness, perfectionism, and control.

Recommendation. A structured interview to diagnose anorexia nervosa is summarized in Table 2. Because the patient will likely deny her symptoms, it is usually necessary to also interview family members or close friends.

Psychiatric comorbidity

Case report continued: A ‘perfectionist.’

School for Ms. J required great effort, and she spent many hours studying. Her upper-middle-class parents described her as “a perfectionist.” The family placed considerable emphasis on doing the “correct” thing.

During adolescence, Ms. J developed a major depressive episode that lasted 4 months. She also developed obsessions and compulsions unrelated to her eating disorder. She obsessively ruminated about the correct things to say in social circumstances and devoted 4 hours per day to cleaning and checking compulsions. She felt she had to wash her car every time before going out; if she could not, she would cancel her social plans.

Table 2

Diagnosis of anorexia nervosa: Questions to ask*

In college, she began abusing alcohol and was arrested once for driving while intoxicated.

Depression is the most common comorbidity in anorexia nervosa. Two-thirds of anorectic patients in a 10-year follow-up study reported a history of major depressive disorder.⁵ Suicide, starvation, and electrolyte imbalance are the three major causes of death. Among severely ill patients who require hospitalization, 10% to 20% die, though the suicide rate is undocumented.

Compulsions. Anorectics’ preoccupations about food and eating rituals have been compared with compulsions, though less than 20% of patients meet diagnostic criteria for obsessive-compulsive disorder.⁶

Substance abuse. Bulimic anorectics report more alcohol and substance use and abuse than restricting anorectics.⁷ The most common substances of abuse are cannabis, cocaine, stimulants, and over-the-counter pills such as diet aids.

Personality disorders. Up to 50% of patients with anorexia nervosa—particularly the binge/purge subtype—have personality disorders. Borderline personality disorder is especially common among binge/purge types,⁸ and avoidant personality disorder is more common among restricting types.

Table 3

Diagnostic signs of emaciation and purging in patients with anorexia nervosa

Personality disorders usually reflect instability in interpersonal relationships, poor self-image, or fluctuating affect. Patients may show a pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation.

Sexuality. Psychosocial and sexual development is often delayed in adolescent anorectics. In adults, interest in sex often plummets with anorexia onset, although binge/purge-type patients occasionally become promiscuous.

Medical signs

Case report continued: Abnormal ECG.

Ms. J was hospitalized after her weight dropped below 75% of normal for her age, height, and body build. She showed signs of electrolyte disturbance, including severe bradycardia (pulse rate 40) and ST-segment abnormalities on ECG.

Clinical signs of emaciation and purging can assist with diagnosis and in making decisions about medical treatment, including hospitalization (Table 3). Patients who purge are often weak and have puffy cheeks or parotid gland enlargement. They may have fainting spells and scars on their hands from stimulating vomiting. Laxative abuse may decrease colon motility and worsen constipation.

Neuroendocrine changes secondary to dieting and weight loss include:

• increased corticotropin-releasing hormone secretion
• blunted diurnal cortisol fluctuation
• decreased follicle-stimulating hormone (FSH) secretion
• impaired growth hormone regulation
• decreased luteinizing hormone (LH) secretion
• mildly decreased triiodothyronine
• erratic vasopressin secretion.

Measuring these changes is unnecessary, as general nutritional rehabilitation with weight gain will correct them.

Neurotransmitter function. Emaciated anorectics have a blunted response to pharmacologic probes for dopamine, reduced CSF norepinephrine turnover, and decreased CSF serotonin. Neuroimaging studies suggest that serotonin dysfunction may persist after weight is restored, although these findings require replication.

Treatment priorities

Effective therapies. Open studies indicate that multidimensional treatment—medical management, psychoeducation, and individual cognitive-behavioral therapy (CBT)—is most effective for anorexia nervosa. The fewer than 10 controlled trials that address anorexia nervosa treatment show:

• the more severe the illness, the more intense the treatment required
• outpatient therapy is most successful in patients who have had the illness <6 months, are not binging and vomiting, and have parents who participate in family therapy.

Hospitalization. An emaciated patient who is irritable, depressed, preoccupied with food, and sleep-deprived is unlikely to make progress toward behavioral change. The first goal, therefore, is to restore her nutritional state to normal.

Severely ill anorectic patients require hospitalization for daily monitoring of weight, calorie intake, urine output, and serum electrolytes and amylase (to assess purging behavior). Hospitalization is indicated for:

• loss of >20% of normal weight for age, height, and bone structure
• >6 months of repeated hospitalizations and underweight
• psychotic depression or serious suicide attempt
• incapacitating obsessions and compulsions, related or not to the eating disorder
• serious comorbid medical conditions, such as edema, hypoproteinemia, severe anemia, cardiac arrhythmia, or hypokalemic alkalosis (serum K+ < 2.5 mEq/L).

Keeping a patient in the hospital long enough to provide effective medical and psychological therapy has become difficult, however, because of medical insurance restrictions (Box). The result: poorer outcomes and increased relapse rates compared with 10 years ago.^9-12

Box

Nutritional rehabilitation and behavior changes can often correct the medical complications of emaciation and purging. Lost bone density is seldom restored, but nutritional rehabilitation can prevent further bone loss.¹³ Women who remain amenorrheic for several years after weight restoration tend to be more psychologically disturbed than those who resume menses rapidly.¹⁴

Cognitive-behavioral therapy

Other authors have discussed CBT for anorexia nervosa.^3,15 In general, the key tasks—operationalizing beliefs, evaluating autonomic thoughts, testing prospective hypotheses, and examining underlying assumptions—are accomplished by assessing anorexia’s distorted cognitions. No satisfactory controlled studies have examined any other type of individual psychotherapy for treating anorexia nervosa.

Alliance building. Patients with anorexia find it difficult to participate in therapeutic relationships. They are terrified of gaining weight and readily drop out of treatment. To build a therapeutic alliance:

• begin by helping the patient develop a history of her significant life events
• proceed slowly, praising her for every small attempt at changing her behavior
• set realistic therapy goals, considering her degree of resistance.

Monitoring. Behavior therapy consists primarily of positive reinforcements for weight gain. For this, we weigh outpatients weekly and inpatients daily. Outpatients are taught to keep diaries of daily food intake, stressful events, and emotional responses to them. The therapist begins each session by examining the patient’s diary with her and discussing how life events affect her eating behavior.

Cognitive restructuring helps patients identify their disturbed cognitions and challenge core beliefs about self-image. In this process, they become aware of their negative thoughts and develop arguments and evidence to support and refute the thoughts’ validity. They then form a reasoned conclusion based on the evidence.

Even if patients do not accept this logical conclusion, we encourage them to behave as if they believe it to be true. By doing this repeatedly, they eventually obtain some symptom relief.

Response-prevention techniques can help stop binging and purging. For example, we may require inpatients to sit together for 1 hour after eating. Because most patients will not vomit in front of each other, they learn how to resist vomiting and eventually experience reduced anxiety without vomiting after a meal.

Problem solving helps patients to reason through difficult food-related or interpersonal situations. The patient states the problem, then generates as many solutions as possible with the therapist’s assistance. She chooses one solution and puts it into effect, usually for 1 week. She then discusses the results with her therapist and decides whether to try another solution.

Family therapy. A family analysis—including a brief psychiatric history and evaluation of interactions—is recommended for all patients who live at home. This analysis can help you decide what type of family therapy or counseling to recommend.

Some families respond well with the parents and patient together in therapy sessions, whereas others are more comfortable with separate counseling. In a recent controlled study, anorectic patients younger than age 18 did equally well whether they were counseled with the family or separately.¹⁶

Brief therapy sessions are sometimes the most effective method to address family issues. When this is not possible, you and the patient can discuss family relationships in individual therapy.

Medications

Many medications have been used to treat anorexia nervosa, though few randomized, placebo-controlled studies exist. Because evidence does not support using psychotropics as monotherapy for anorexia nervosa, medication is considered adjunctive to CBT.

Chlorpromazine can help the hospitalized, severely ill patient who is overwhelmed with uncontrollable behavioral rituals and thoughts of losing weight. This antipsychotic helps reduce anorectic preoccupations and anxiety and helps make patients more amenable to therapy.

Start chlorpromazine at 10 mg tid and increase gradually until the patient can eat without extreme anxiety. Usual maximum dosage is 50 mg tid. Monitor blood pressure, tardive dyskinesia, and decreased white blood cell count.

Olanzapine may help induce weight gain and reduce anxiety in anorectic patients.¹⁷ Controlled and open-label studies are under way.

We start olanzapine at 2.5 mg/d and increase gradually to 10 or 15 mg/d. At this dosage, patients’ anxiety about eating is usually substantially reduced. Sedation is the most common side effect.

Anorexia patients often refuse to take olanzapine for fear of weight gain. If a patient’s emaciation is life-threatening, we may seek court permission to medicate her involuntarily. We reassure her that we will discontinue olanzapine when she reaches her target weight.

Serotonin in anorexia. Central serotonin pathways modulate feeding behavior. Serotonin antagonists—such as cyproheptadine—increase food intake and weight gain, whereas serotonin agonists—such as selective serotonin reuptake inhibitors (SSRIs)—decrease food intake.

Serotonin pathways also may modulate obsessive-compulsive and impulsive behaviors. Both serotonin agonists and antagonists can be useful adjuncts in treating anorexia nervosa.

In a double-blind, placebo-controlled trial, cyproheptadine, 4 to 8 mg tid, was associated with weight gain and reduced depressive symptoms in anorexia nervosa patients.¹⁸ Unlike tricyclic antidepressants, cyproheptadine does not reduce blood pressure or increase heart rate, which makes it attractive for emaciated anorectic patients. Dosages up to 28 mg/d can be used safely.

The SSRI fluoxetine may help prevent weight loss relapse in anorexia nervosa and reduce obsessive-compulsive behaviors.¹⁹ In open studies of low-weight anorectics, however, fluoxetine had little impact on weight or other clinically meaningful variables.²⁰ Thus, this agent is recommended for preventing weight-loss relapse only in patients who are within 10% to 15% of ideal body weight.

Outpatient care

Case report continued: Ongoing therapy

During hospitalization, Ms. J participated in all therapeutic modalities but had difficulty eating enough to gain weight. She reached her target weight of 127 lbs in about 7 weeks but gained no sense of purpose in life.

She is starting an intensive outpatient program using CBT to maintain her weight and further address the core psychopathology of her illness. Her maintenance therapy includes attending Alcoholics Anonymous meetings, ongoing fluoxetine (20 mg/d) to prevent weight-loss relapse, and CBT for obsessions and compulsions not related to her eating disorder.

Related resources

• Halmi KA. Eating disorders: Anorexia, bulimia nervosa and obesity. In: Hales RE, Yudofsky SC (eds). Textbook of clinical psychiatry, 4th ed. Washington, DC: American Psychiatric Publishing, 2003:1001-21.
• Academy of Eating Disorders. www.aedweb.org
• Anorexia Nervosa & Associated Disorders (ANAD). www.anad.org

Drug brand names

• Chlorpromazine • Thorazine
• Cyproheptadine • Periactin
• Fluoxetine • Prozac
• Olanzapine • Zyprexa

Disclosure

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

Ms. J started losing weight deliberately at age 14 while attending boarding school. She lost 25 lbs by jogging 6 miles per day, exercising another 2 hours, avoiding meat, abusing laxatives, and drinking large quantities of coffee.

She was referred to a school counselor because of her weight loss and returned home. She was happier at a local high school and recovered to normal weight. In college, however, she reverted to compulsive exercising and preoccupation with her weight after the break-up of her first intimate relationship.

Now at age 22, Ms. J has persistently failed to gain weight during outpatient therapy for anorexia nervosa. At 5′7″ she weighs 98 lbs. On the day she was to be hospitalized involuntarily, she took 25 diphenhydramine tablets, which her psychiatrist viewed as a suicide threat. The overdose was treated in the emergency room with ipecac syrup, and she was admitted for inpatient eating disorder treatment.

Like Ms. J, patients with anorexia nervosa resist treatment and deny having most diagnostic signs and symptoms. Based on the evidence and my 30 years of treating anorectic patients,¹ this article offers suggestions to help you:

• gather accurate histories from patients and their families
• identify common psychiatric comorbidities
• gain the patient’s trust during treatment
• provide effective dual therapy, with cognitive-behavioral and pharmacologic components.

Table 1

Diagnostic criteria for anorexia nervosa

Making the diagnosis

Anorexia nervosa is characterized by underweight, fear of gaining weight, disturbed body concept, and amenorrhea (Table 1). Its core psychological symptoms have been described as:

• relentless pursuit of thinness
• denial of cachexia
• and feelings of general ineffectiveness.²

The patient may say she feels fat even though emaciated or that parts of her body are too large. This disturbed experience of body weight or shape may represent sublimation and displacement for feelings of inadequacy. Because anorectic patients stay thin so effectively, they may feel a sense of accomplishment by evaluating themselves in terms of their thinness. Cognitive therapy focuses on correcting patients’ pervasive sense of inadequacy, as manifest in maturity fears and lack of confidence in coping with life’s problems.³

Subtypes. Anorexia nervosa has two subtypes—restricting and binge eating/purging—that differ in behavioral and medical symptoms.⁴ Patients with binge eating/purging show:

• higher rates of impulsivity (suicide attempts, self-mutilation, stealing, and alcohol and other substance abuse)
• more-prevalent impulsive personality disorders (borderline personality disorder, hysterical personality disorder)
• medical problems caused by purging.

Restricting-type patients are often dependent and submissive, with difficulty separating from parents. These patients may be preoccupied with orderliness, perfectionism, and control.

Recommendation. A structured interview to diagnose anorexia nervosa is summarized in Table 2. Because the patient will likely deny her symptoms, it is usually necessary to also interview family members or close friends.

Psychiatric comorbidity

Case report continued: A ‘perfectionist.’

School for Ms. J required great effort, and she spent many hours studying. Her upper-middle-class parents described her as “a perfectionist.” The family placed considerable emphasis on doing the “correct” thing.

During adolescence, Ms. J developed a major depressive episode that lasted 4 months. She also developed obsessions and compulsions unrelated to her eating disorder. She obsessively ruminated about the correct things to say in social circumstances and devoted 4 hours per day to cleaning and checking compulsions. She felt she had to wash her car every time before going out; if she could not, she would cancel her social plans.

Table 2

Diagnosis of anorexia nervosa: Questions to ask*

In college, she began abusing alcohol and was arrested once for driving while intoxicated.

Depression is the most common comorbidity in anorexia nervosa. Two-thirds of anorectic patients in a 10-year follow-up study reported a history of major depressive disorder.⁵ Suicide, starvation, and electrolyte imbalance are the three major causes of death. Among severely ill patients who require hospitalization, 10% to 20% die, though the suicide rate is undocumented.

Compulsions. Anorectics’ preoccupations about food and eating rituals have been compared with compulsions, though less than 20% of patients meet diagnostic criteria for obsessive-compulsive disorder.⁶

Substance abuse. Bulimic anorectics report more alcohol and substance use and abuse than restricting anorectics.⁷ The most common substances of abuse are cannabis, cocaine, stimulants, and over-the-counter pills such as diet aids.

Personality disorders. Up to 50% of patients with anorexia nervosa—particularly the binge/purge subtype—have personality disorders. Borderline personality disorder is especially common among binge/purge types,⁸ and avoidant personality disorder is more common among restricting types.

Table 3

Diagnostic signs of emaciation and purging in patients with anorexia nervosa

Personality disorders usually reflect instability in interpersonal relationships, poor self-image, or fluctuating affect. Patients may show a pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation.

Sexuality. Psychosocial and sexual development is often delayed in adolescent anorectics. In adults, interest in sex often plummets with anorexia onset, although binge/purge-type patients occasionally become promiscuous.

Medical signs

Case report continued: Abnormal ECG.

Ms. J was hospitalized after her weight dropped below 75% of normal for her age, height, and body build. She showed signs of electrolyte disturbance, including severe bradycardia (pulse rate 40) and ST-segment abnormalities on ECG.

Clinical signs of emaciation and purging can assist with diagnosis and in making decisions about medical treatment, including hospitalization (Table 3). Patients who purge are often weak and have puffy cheeks or parotid gland enlargement. They may have fainting spells and scars on their hands from stimulating vomiting. Laxative abuse may decrease colon motility and worsen constipation.

Neuroendocrine changes secondary to dieting and weight loss include:

• increased corticotropin-releasing hormone secretion
• blunted diurnal cortisol fluctuation
• decreased follicle-stimulating hormone (FSH) secretion
• impaired growth hormone regulation
• decreased luteinizing hormone (LH) secretion
• mildly decreased triiodothyronine
• erratic vasopressin secretion.

Measuring these changes is unnecessary, as general nutritional rehabilitation with weight gain will correct them.

Neurotransmitter function. Emaciated anorectics have a blunted response to pharmacologic probes for dopamine, reduced CSF norepinephrine turnover, and decreased CSF serotonin. Neuroimaging studies suggest that serotonin dysfunction may persist after weight is restored, although these findings require replication.

Treatment priorities

Effective therapies. Open studies indicate that multidimensional treatment—medical management, psychoeducation, and individual cognitive-behavioral therapy (CBT)—is most effective for anorexia nervosa. The fewer than 10 controlled trials that address anorexia nervosa treatment show:

• the more severe the illness, the more intense the treatment required
• outpatient therapy is most successful in patients who have had the illness <6 months, are not binging and vomiting, and have parents who participate in family therapy.

Hospitalization. An emaciated patient who is irritable, depressed, preoccupied with food, and sleep-deprived is unlikely to make progress toward behavioral change. The first goal, therefore, is to restore her nutritional state to normal.

Severely ill anorectic patients require hospitalization for daily monitoring of weight, calorie intake, urine output, and serum electrolytes and amylase (to assess purging behavior). Hospitalization is indicated for:

• loss of >20% of normal weight for age, height, and bone structure
• >6 months of repeated hospitalizations and underweight
• psychotic depression or serious suicide attempt
• incapacitating obsessions and compulsions, related or not to the eating disorder
• serious comorbid medical conditions, such as edema, hypoproteinemia, severe anemia, cardiac arrhythmia, or hypokalemic alkalosis (serum K+ < 2.5 mEq/L).

Keeping a patient in the hospital long enough to provide effective medical and psychological therapy has become difficult, however, because of medical insurance restrictions (Box). The result: poorer outcomes and increased relapse rates compared with 10 years ago.^9-12

Box

Nutritional rehabilitation and behavior changes can often correct the medical complications of emaciation and purging. Lost bone density is seldom restored, but nutritional rehabilitation can prevent further bone loss.¹³ Women who remain amenorrheic for several years after weight restoration tend to be more psychologically disturbed than those who resume menses rapidly.¹⁴

Cognitive-behavioral therapy

Other authors have discussed CBT for anorexia nervosa.^3,15 In general, the key tasks—operationalizing beliefs, evaluating autonomic thoughts, testing prospective hypotheses, and examining underlying assumptions—are accomplished by assessing anorexia’s distorted cognitions. No satisfactory controlled studies have examined any other type of individual psychotherapy for treating anorexia nervosa.

Alliance building. Patients with anorexia find it difficult to participate in therapeutic relationships. They are terrified of gaining weight and readily drop out of treatment. To build a therapeutic alliance:

• begin by helping the patient develop a history of her significant life events
• proceed slowly, praising her for every small attempt at changing her behavior
• set realistic therapy goals, considering her degree of resistance.

Monitoring. Behavior therapy consists primarily of positive reinforcements for weight gain. For this, we weigh outpatients weekly and inpatients daily. Outpatients are taught to keep diaries of daily food intake, stressful events, and emotional responses to them. The therapist begins each session by examining the patient’s diary with her and discussing how life events affect her eating behavior.

Cognitive restructuring helps patients identify their disturbed cognitions and challenge core beliefs about self-image. In this process, they become aware of their negative thoughts and develop arguments and evidence to support and refute the thoughts’ validity. They then form a reasoned conclusion based on the evidence.

Even if patients do not accept this logical conclusion, we encourage them to behave as if they believe it to be true. By doing this repeatedly, they eventually obtain some symptom relief.

Response-prevention techniques can help stop binging and purging. For example, we may require inpatients to sit together for 1 hour after eating. Because most patients will not vomit in front of each other, they learn how to resist vomiting and eventually experience reduced anxiety without vomiting after a meal.

Problem solving helps patients to reason through difficult food-related or interpersonal situations. The patient states the problem, then generates as many solutions as possible with the therapist’s assistance. She chooses one solution and puts it into effect, usually for 1 week. She then discusses the results with her therapist and decides whether to try another solution.

Family therapy. A family analysis—including a brief psychiatric history and evaluation of interactions—is recommended for all patients who live at home. This analysis can help you decide what type of family therapy or counseling to recommend.

Some families respond well with the parents and patient together in therapy sessions, whereas others are more comfortable with separate counseling. In a recent controlled study, anorectic patients younger than age 18 did equally well whether they were counseled with the family or separately.¹⁶

Brief therapy sessions are sometimes the most effective method to address family issues. When this is not possible, you and the patient can discuss family relationships in individual therapy.

Medications

Many medications have been used to treat anorexia nervosa, though few randomized, placebo-controlled studies exist. Because evidence does not support using psychotropics as monotherapy for anorexia nervosa, medication is considered adjunctive to CBT.

Chlorpromazine can help the hospitalized, severely ill patient who is overwhelmed with uncontrollable behavioral rituals and thoughts of losing weight. This antipsychotic helps reduce anorectic preoccupations and anxiety and helps make patients more amenable to therapy.

Start chlorpromazine at 10 mg tid and increase gradually until the patient can eat without extreme anxiety. Usual maximum dosage is 50 mg tid. Monitor blood pressure, tardive dyskinesia, and decreased white blood cell count.

Olanzapine may help induce weight gain and reduce anxiety in anorectic patients.¹⁷ Controlled and open-label studies are under way.

We start olanzapine at 2.5 mg/d and increase gradually to 10 or 15 mg/d. At this dosage, patients’ anxiety about eating is usually substantially reduced. Sedation is the most common side effect.

Anorexia patients often refuse to take olanzapine for fear of weight gain. If a patient’s emaciation is life-threatening, we may seek court permission to medicate her involuntarily. We reassure her that we will discontinue olanzapine when she reaches her target weight.

Serotonin in anorexia. Central serotonin pathways modulate feeding behavior. Serotonin antagonists—such as cyproheptadine—increase food intake and weight gain, whereas serotonin agonists—such as selective serotonin reuptake inhibitors (SSRIs)—decrease food intake.

Serotonin pathways also may modulate obsessive-compulsive and impulsive behaviors. Both serotonin agonists and antagonists can be useful adjuncts in treating anorexia nervosa.

In a double-blind, placebo-controlled trial, cyproheptadine, 4 to 8 mg tid, was associated with weight gain and reduced depressive symptoms in anorexia nervosa patients.¹⁸ Unlike tricyclic antidepressants, cyproheptadine does not reduce blood pressure or increase heart rate, which makes it attractive for emaciated anorectic patients. Dosages up to 28 mg/d can be used safely.

The SSRI fluoxetine may help prevent weight loss relapse in anorexia nervosa and reduce obsessive-compulsive behaviors.¹⁹ In open studies of low-weight anorectics, however, fluoxetine had little impact on weight or other clinically meaningful variables.²⁰ Thus, this agent is recommended for preventing weight-loss relapse only in patients who are within 10% to 15% of ideal body weight.

Outpatient care

Case report continued: Ongoing therapy

During hospitalization, Ms. J participated in all therapeutic modalities but had difficulty eating enough to gain weight. She reached her target weight of 127 lbs in about 7 weeks but gained no sense of purpose in life.

She is starting an intensive outpatient program using CBT to maintain her weight and further address the core psychopathology of her illness. Her maintenance therapy includes attending Alcoholics Anonymous meetings, ongoing fluoxetine (20 mg/d) to prevent weight-loss relapse, and CBT for obsessions and compulsions not related to her eating disorder.

Related resources

• Halmi KA. Eating disorders: Anorexia, bulimia nervosa and obesity. In: Hales RE, Yudofsky SC (eds). Textbook of clinical psychiatry, 4th ed. Washington, DC: American Psychiatric Publishing, 2003:1001-21.
• Academy of Eating Disorders. www.aedweb.org
• Anorexia Nervosa & Associated Disorders (ANAD). www.anad.org

Drug brand names

• Chlorpromazine • Thorazine
• Cyproheptadine • Periactin
• Fluoxetine • Prozac
• Olanzapine • Zyprexa

Disclosure

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

Ms. J started losing weight deliberately at age 14 while attending boarding school. She lost 25 lbs by jogging 6 miles per day, exercising another 2 hours, avoiding meat, abusing laxatives, and drinking large quantities of coffee.

She was referred to a school counselor because of her weight loss and returned home. She was happier at a local high school and recovered to normal weight. In college, however, she reverted to compulsive exercising and preoccupation with her weight after the break-up of her first intimate relationship.

Now at age 22, Ms. J has persistently failed to gain weight during outpatient therapy for anorexia nervosa. At 5′7″ she weighs 98 lbs. On the day she was to be hospitalized involuntarily, she took 25 diphenhydramine tablets, which her psychiatrist viewed as a suicide threat. The overdose was treated in the emergency room with ipecac syrup, and she was admitted for inpatient eating disorder treatment.

Like Ms. J, patients with anorexia nervosa resist treatment and deny having most diagnostic signs and symptoms. Based on the evidence and my 30 years of treating anorectic patients,¹ this article offers suggestions to help you:

• gather accurate histories from patients and their families
• identify common psychiatric comorbidities
• gain the patient’s trust during treatment
• provide effective dual therapy, with cognitive-behavioral and pharmacologic components.

Table 1

Diagnostic criteria for anorexia nervosa

Making the diagnosis

Anorexia nervosa is characterized by underweight, fear of gaining weight, disturbed body concept, and amenorrhea (Table 1). Its core psychological symptoms have been described as:

• relentless pursuit of thinness
• denial of cachexia
• and feelings of general ineffectiveness.²

The patient may say she feels fat even though emaciated or that parts of her body are too large. This disturbed experience of body weight or shape may represent sublimation and displacement for feelings of inadequacy. Because anorectic patients stay thin so effectively, they may feel a sense of accomplishment by evaluating themselves in terms of their thinness. Cognitive therapy focuses on correcting patients’ pervasive sense of inadequacy, as manifest in maturity fears and lack of confidence in coping with life’s problems.³

Subtypes. Anorexia nervosa has two subtypes—restricting and binge eating/purging—that differ in behavioral and medical symptoms.⁴ Patients with binge eating/purging show:

• higher rates of impulsivity (suicide attempts, self-mutilation, stealing, and alcohol and other substance abuse)
• more-prevalent impulsive personality disorders (borderline personality disorder, hysterical personality disorder)
• medical problems caused by purging.

Restricting-type patients are often dependent and submissive, with difficulty separating from parents. These patients may be preoccupied with orderliness, perfectionism, and control.

Recommendation. A structured interview to diagnose anorexia nervosa is summarized in Table 2. Because the patient will likely deny her symptoms, it is usually necessary to also interview family members or close friends.

Psychiatric comorbidity

Case report continued: A ‘perfectionist.’

School for Ms. J required great effort, and she spent many hours studying. Her upper-middle-class parents described her as “a perfectionist.” The family placed considerable emphasis on doing the “correct” thing.

During adolescence, Ms. J developed a major depressive episode that lasted 4 months. She also developed obsessions and compulsions unrelated to her eating disorder. She obsessively ruminated about the correct things to say in social circumstances and devoted 4 hours per day to cleaning and checking compulsions. She felt she had to wash her car every time before going out; if she could not, she would cancel her social plans.

Table 2

Diagnosis of anorexia nervosa: Questions to ask*

In college, she began abusing alcohol and was arrested once for driving while intoxicated.

Depression is the most common comorbidity in anorexia nervosa. Two-thirds of anorectic patients in a 10-year follow-up study reported a history of major depressive disorder.⁵ Suicide, starvation, and electrolyte imbalance are the three major causes of death. Among severely ill patients who require hospitalization, 10% to 20% die, though the suicide rate is undocumented.

Compulsions. Anorectics’ preoccupations about food and eating rituals have been compared with compulsions, though less than 20% of patients meet diagnostic criteria for obsessive-compulsive disorder.⁶

Substance abuse. Bulimic anorectics report more alcohol and substance use and abuse than restricting anorectics.⁷ The most common substances of abuse are cannabis, cocaine, stimulants, and over-the-counter pills such as diet aids.

Personality disorders. Up to 50% of patients with anorexia nervosa—particularly the binge/purge subtype—have personality disorders. Borderline personality disorder is especially common among binge/purge types,⁸ and avoidant personality disorder is more common among restricting types.

Table 3

Diagnostic signs of emaciation and purging in patients with anorexia nervosa

Personality disorders usually reflect instability in interpersonal relationships, poor self-image, or fluctuating affect. Patients may show a pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation.

Sexuality. Psychosocial and sexual development is often delayed in adolescent anorectics. In adults, interest in sex often plummets with anorexia onset, although binge/purge-type patients occasionally become promiscuous.

Medical signs

Case report continued: Abnormal ECG.

Ms. J was hospitalized after her weight dropped below 75% of normal for her age, height, and body build. She showed signs of electrolyte disturbance, including severe bradycardia (pulse rate 40) and ST-segment abnormalities on ECG.

Clinical signs of emaciation and purging can assist with diagnosis and in making decisions about medical treatment, including hospitalization (Table 3). Patients who purge are often weak and have puffy cheeks or parotid gland enlargement. They may have fainting spells and scars on their hands from stimulating vomiting. Laxative abuse may decrease colon motility and worsen constipation.

Neuroendocrine changes secondary to dieting and weight loss include:

• increased corticotropin-releasing hormone secretion
• blunted diurnal cortisol fluctuation
• decreased follicle-stimulating hormone (FSH) secretion
• impaired growth hormone regulation
• decreased luteinizing hormone (LH) secretion
• mildly decreased triiodothyronine
• erratic vasopressin secretion.

Measuring these changes is unnecessary, as general nutritional rehabilitation with weight gain will correct them.

Neurotransmitter function. Emaciated anorectics have a blunted response to pharmacologic probes for dopamine, reduced CSF norepinephrine turnover, and decreased CSF serotonin. Neuroimaging studies suggest that serotonin dysfunction may persist after weight is restored, although these findings require replication.

Treatment priorities

Effective therapies. Open studies indicate that multidimensional treatment—medical management, psychoeducation, and individual cognitive-behavioral therapy (CBT)—is most effective for anorexia nervosa. The fewer than 10 controlled trials that address anorexia nervosa treatment show:

• the more severe the illness, the more intense the treatment required
• outpatient therapy is most successful in patients who have had the illness <6 months, are not binging and vomiting, and have parents who participate in family therapy.

Hospitalization. An emaciated patient who is irritable, depressed, preoccupied with food, and sleep-deprived is unlikely to make progress toward behavioral change. The first goal, therefore, is to restore her nutritional state to normal.

Severely ill anorectic patients require hospitalization for daily monitoring of weight, calorie intake, urine output, and serum electrolytes and amylase (to assess purging behavior). Hospitalization is indicated for:

• loss of >20% of normal weight for age, height, and bone structure
• >6 months of repeated hospitalizations and underweight
• psychotic depression or serious suicide attempt
• incapacitating obsessions and compulsions, related or not to the eating disorder
• serious comorbid medical conditions, such as edema, hypoproteinemia, severe anemia, cardiac arrhythmia, or hypokalemic alkalosis (serum K+ < 2.5 mEq/L).

Keeping a patient in the hospital long enough to provide effective medical and psychological therapy has become difficult, however, because of medical insurance restrictions (Box). The result: poorer outcomes and increased relapse rates compared with 10 years ago.^9-12

Box

Nutritional rehabilitation and behavior changes can often correct the medical complications of emaciation and purging. Lost bone density is seldom restored, but nutritional rehabilitation can prevent further bone loss.¹³ Women who remain amenorrheic for several years after weight restoration tend to be more psychologically disturbed than those who resume menses rapidly.¹⁴

Cognitive-behavioral therapy

Other authors have discussed CBT for anorexia nervosa.^3,15 In general, the key tasks—operationalizing beliefs, evaluating autonomic thoughts, testing prospective hypotheses, and examining underlying assumptions—are accomplished by assessing anorexia’s distorted cognitions. No satisfactory controlled studies have examined any other type of individual psychotherapy for treating anorexia nervosa.

Alliance building. Patients with anorexia find it difficult to participate in therapeutic relationships. They are terrified of gaining weight and readily drop out of treatment. To build a therapeutic alliance:

• begin by helping the patient develop a history of her significant life events
• proceed slowly, praising her for every small attempt at changing her behavior
• set realistic therapy goals, considering her degree of resistance.

Monitoring. Behavior therapy consists primarily of positive reinforcements for weight gain. For this, we weigh outpatients weekly and inpatients daily. Outpatients are taught to keep diaries of daily food intake, stressful events, and emotional responses to them. The therapist begins each session by examining the patient’s diary with her and discussing how life events affect her eating behavior.

Cognitive restructuring helps patients identify their disturbed cognitions and challenge core beliefs about self-image. In this process, they become aware of their negative thoughts and develop arguments and evidence to support and refute the thoughts’ validity. They then form a reasoned conclusion based on the evidence.

Even if patients do not accept this logical conclusion, we encourage them to behave as if they believe it to be true. By doing this repeatedly, they eventually obtain some symptom relief.

Response-prevention techniques can help stop binging and purging. For example, we may require inpatients to sit together for 1 hour after eating. Because most patients will not vomit in front of each other, they learn how to resist vomiting and eventually experience reduced anxiety without vomiting after a meal.

Problem solving helps patients to reason through difficult food-related or interpersonal situations. The patient states the problem, then generates as many solutions as possible with the therapist’s assistance. She chooses one solution and puts it into effect, usually for 1 week. She then discusses the results with her therapist and decides whether to try another solution.

Family therapy. A family analysis—including a brief psychiatric history and evaluation of interactions—is recommended for all patients who live at home. This analysis can help you decide what type of family therapy or counseling to recommend.

Some families respond well with the parents and patient together in therapy sessions, whereas others are more comfortable with separate counseling. In a recent controlled study, anorectic patients younger than age 18 did equally well whether they were counseled with the family or separately.¹⁶

Brief therapy sessions are sometimes the most effective method to address family issues. When this is not possible, you and the patient can discuss family relationships in individual therapy.

Medications

Many medications have been used to treat anorexia nervosa, though few randomized, placebo-controlled studies exist. Because evidence does not support using psychotropics as monotherapy for anorexia nervosa, medication is considered adjunctive to CBT.

Chlorpromazine can help the hospitalized, severely ill patient who is overwhelmed with uncontrollable behavioral rituals and thoughts of losing weight. This antipsychotic helps reduce anorectic preoccupations and anxiety and helps make patients more amenable to therapy.

Start chlorpromazine at 10 mg tid and increase gradually until the patient can eat without extreme anxiety. Usual maximum dosage is 50 mg tid. Monitor blood pressure, tardive dyskinesia, and decreased white blood cell count.

Olanzapine may help induce weight gain and reduce anxiety in anorectic patients.¹⁷ Controlled and open-label studies are under way.

We start olanzapine at 2.5 mg/d and increase gradually to 10 or 15 mg/d. At this dosage, patients’ anxiety about eating is usually substantially reduced. Sedation is the most common side effect.

Anorexia patients often refuse to take olanzapine for fear of weight gain. If a patient’s emaciation is life-threatening, we may seek court permission to medicate her involuntarily. We reassure her that we will discontinue olanzapine when she reaches her target weight.

Serotonin in anorexia. Central serotonin pathways modulate feeding behavior. Serotonin antagonists—such as cyproheptadine—increase food intake and weight gain, whereas serotonin agonists—such as selective serotonin reuptake inhibitors (SSRIs)—decrease food intake.

Serotonin pathways also may modulate obsessive-compulsive and impulsive behaviors. Both serotonin agonists and antagonists can be useful adjuncts in treating anorexia nervosa.

In a double-blind, placebo-controlled trial, cyproheptadine, 4 to 8 mg tid, was associated with weight gain and reduced depressive symptoms in anorexia nervosa patients.¹⁸ Unlike tricyclic antidepressants, cyproheptadine does not reduce blood pressure or increase heart rate, which makes it attractive for emaciated anorectic patients. Dosages up to 28 mg/d can be used safely.

The SSRI fluoxetine may help prevent weight loss relapse in anorexia nervosa and reduce obsessive-compulsive behaviors.¹⁹ In open studies of low-weight anorectics, however, fluoxetine had little impact on weight or other clinically meaningful variables.²⁰ Thus, this agent is recommended for preventing weight-loss relapse only in patients who are within 10% to 15% of ideal body weight.

Outpatient care

Case report continued: Ongoing therapy

During hospitalization, Ms. J participated in all therapeutic modalities but had difficulty eating enough to gain weight. She reached her target weight of 127 lbs in about 7 weeks but gained no sense of purpose in life.

She is starting an intensive outpatient program using CBT to maintain her weight and further address the core psychopathology of her illness. Her maintenance therapy includes attending Alcoholics Anonymous meetings, ongoing fluoxetine (20 mg/d) to prevent weight-loss relapse, and CBT for obsessions and compulsions not related to her eating disorder.

Related resources

• Halmi KA. Eating disorders: Anorexia, bulimia nervosa and obesity. In: Hales RE, Yudofsky SC (eds). Textbook of clinical psychiatry, 4th ed. Washington, DC: American Psychiatric Publishing, 2003:1001-21.
• Academy of Eating Disorders. www.aedweb.org
• Anorexia Nervosa & Associated Disorders (ANAD). www.anad.org

Drug brand names

• Chlorpromazine • Thorazine
• Cyproheptadine • Periactin
• Fluoxetine • Prozac
• Olanzapine • Zyprexa

Disclosure

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

Supplement Editors:
Nancy Foldvary-Schaefer, DO, and Martha J. Morrell, MD

Contents

Introduction
Nancy Foldvary-Schaefer, DO, and Martha J. Morrell, MD

Cellular and molecular effects of steroid hormones on CNS excitability
Sheryl S. Smith, PhD, and Catherine S. Woolley, PhD

Hormones and seizures
Nancy Foldvary-Schaefer, DO; Cynthia Harden, MD; Andrew Herzog, MD; and Tommaso Falcone, MD

Reproductive disturbances in patients with epilepsy
Martha J. Morrell, MD, and Georgia D. Montouris, MD

Risks and management of pregnancy in women with epilepsy
Mark S. Yerby, MD, MPH; Peter Kaplan, MB; and Teresa Tran, MD

Neurodevelopmental outcomes of children born to mothers with epilepsy
Kimford J. Meador, MD, and Mary L. Zupanc, MD

Bone disease associated with antiepileptic drugs
Alison M. Pack, MD; Barry Gidal, PharmD; and Blanca Vazquez, MD

Recommendations for the care of women with epilepsy
Patricia E. Penovich, MD; Karen E. Eck, MS, FNP; and Vasiliki V. Economou, MD

Supplement Editors:
Nancy Foldvary-Schaefer, DO, and Martha J. Morrell, MD

Contents

Introduction
Nancy Foldvary-Schaefer, DO, and Martha J. Morrell, MD

Cellular and molecular effects of steroid hormones on CNS excitability
Sheryl S. Smith, PhD, and Catherine S. Woolley, PhD

Hormones and seizures
Nancy Foldvary-Schaefer, DO; Cynthia Harden, MD; Andrew Herzog, MD; and Tommaso Falcone, MD

Reproductive disturbances in patients with epilepsy
Martha J. Morrell, MD, and Georgia D. Montouris, MD

Risks and management of pregnancy in women with epilepsy
Mark S. Yerby, MD, MPH; Peter Kaplan, MB; and Teresa Tran, MD

Neurodevelopmental outcomes of children born to mothers with epilepsy
Kimford J. Meador, MD, and Mary L. Zupanc, MD

Bone disease associated with antiepileptic drugs
Alison M. Pack, MD; Barry Gidal, PharmD; and Blanca Vazquez, MD

Recommendations for the care of women with epilepsy
Patricia E. Penovich, MD; Karen E. Eck, MS, FNP; and Vasiliki V. Economou, MD

Supplement Editors:
Nancy Foldvary-Schaefer, DO, and Martha J. Morrell, MD

Contents

Introduction
Nancy Foldvary-Schaefer, DO, and Martha J. Morrell, MD

Cellular and molecular effects of steroid hormones on CNS excitability
Sheryl S. Smith, PhD, and Catherine S. Woolley, PhD

Hormones and seizures
Nancy Foldvary-Schaefer, DO; Cynthia Harden, MD; Andrew Herzog, MD; and Tommaso Falcone, MD

Reproductive disturbances in patients with epilepsy
Martha J. Morrell, MD, and Georgia D. Montouris, MD

Risks and management of pregnancy in women with epilepsy
Mark S. Yerby, MD, MPH; Peter Kaplan, MB; and Teresa Tran, MD

Neurodevelopmental outcomes of children born to mothers with epilepsy
Kimford J. Meador, MD, and Mary L. Zupanc, MD

Bone disease associated with antiepileptic drugs
Alison M. Pack, MD; Barry Gidal, PharmD; and Blanca Vazquez, MD

Recommendations for the care of women with epilepsy
Patricia E. Penovich, MD; Karen E. Eck, MS, FNP; and Vasiliki V. Economou, MD

Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:

• Differentiate medical from psychiatric causes of patients’ distress.
• Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
• Start low and go slow when titrating dosages.

Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.

Algorithm Treating behavioral symptoms in patients with dementia

Dementia’s behavioral symptoms

An International Psychogeriatric Association consensus statement¹ grouped dementia’s behavioral and psychological symptoms into two types:

• those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
• those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.

These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.

Rule out a medical cause

Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:

• A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
• In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
• Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.

Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.

Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.

Use antipsychotics as adjuncts

Psychosocial interventions. After medical causes have been ruled out, consensus guidelines² recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.³

Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.

When prescribing atypicals, remember that older adults:

• are more sensitive to side effects than younger adults
• require lower starting and target dosages
• exhibit heterogeneity of response.

Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).^4-11

Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:

• risperidone, 0.5 to 1.5 mg/d¹²
• olanzapine, 5 to 10 mg/d¹³
• quetiapine, 25 to 350 mg/d¹⁴ (Table 2).^15,16

Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.

Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:

• mood stabilizers such as divalproex¹⁷ or carbamazepine¹⁸
• cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.¹⁹

Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.²⁰

Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.

Table 1

Suggested psychosocial interventions for older patients with dementia

Antipsychotic side effects

Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).²¹

Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,²² and rates are much higher for middle-aged and older adults receiving chronic therapy:

• 29% after 1 year
• 50% after 2 years
• 63% after 3 years.²³

In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.

Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).

Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.²⁴ Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.

Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.

Start low, go slow

Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.²⁵ However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).

Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.

Risperidone has been used to treat agitation in older patients with dementia in two small studies:

In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.²⁶ CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.²⁷

A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:

• Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
• BEHAVE-AD psychosis subscale scores
• BEHAVE-AD aggressiveness scores
• CMAI verbal and aggression scores.

Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.¹²

Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:

• mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
• CMAI score decreased by 32%, compared with 18% in the placebo group.

EPS were more severe with haloperidol than with risperidone or placebo.²⁸

Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.

Box

Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.^12,29

Table 2

Antipsychotic side effects and dosages in older patients with dementia*

Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel² recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.

Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.

Saterlee et al³⁰ compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.

In a later study,¹³ nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.

Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.

Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.

Quetiapine. One open-label study¹⁴ examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.

Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.

Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).

EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.

Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.

Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,³¹ ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.

Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.

Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,³² 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.

At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.

Related resources

• Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
• Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
• Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Donepezil • Aricept
• Galantamine • Reminyl
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Valproate • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.

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

Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.

Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:

• Differentiate medical from psychiatric causes of patients’ distress.
• Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
• Start low and go slow when titrating dosages.

Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.

Algorithm Treating behavioral symptoms in patients with dementia

Dementia’s behavioral symptoms

An International Psychogeriatric Association consensus statement¹ grouped dementia’s behavioral and psychological symptoms into two types:

• those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
• those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.

These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.

Rule out a medical cause

Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:

• A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
• In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
• Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.

Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.

Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.

Use antipsychotics as adjuncts

Psychosocial interventions. After medical causes have been ruled out, consensus guidelines² recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.³

Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.

When prescribing atypicals, remember that older adults:

• are more sensitive to side effects than younger adults
• require lower starting and target dosages
• exhibit heterogeneity of response.

Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).^4-11

Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:

• risperidone, 0.5 to 1.5 mg/d¹²
• olanzapine, 5 to 10 mg/d¹³
• quetiapine, 25 to 350 mg/d¹⁴ (Table 2).^15,16

Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.

Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:

• mood stabilizers such as divalproex¹⁷ or carbamazepine¹⁸
• cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.¹⁹

Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.²⁰

Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.

Table 1

Suggested psychosocial interventions for older patients with dementia

Antipsychotic side effects

Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).²¹

Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,²² and rates are much higher for middle-aged and older adults receiving chronic therapy:

• 29% after 1 year
• 50% after 2 years
• 63% after 3 years.²³

In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.

Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).

Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.²⁴ Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.

Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.

Start low, go slow

Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.²⁵ However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).

Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.

Risperidone has been used to treat agitation in older patients with dementia in two small studies:

In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.²⁶ CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.²⁷

A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:

• Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
• BEHAVE-AD psychosis subscale scores
• BEHAVE-AD aggressiveness scores
• CMAI verbal and aggression scores.

Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.¹²

Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:

• mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
• CMAI score decreased by 32%, compared with 18% in the placebo group.

EPS were more severe with haloperidol than with risperidone or placebo.²⁸

Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.

Box

Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.^12,29

Table 2

Antipsychotic side effects and dosages in older patients with dementia*

Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel² recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.

Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.

Saterlee et al³⁰ compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.

In a later study,¹³ nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.

Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.

Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.

Quetiapine. One open-label study¹⁴ examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.

Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.

Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).

EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.

Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.

Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,³¹ ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.

Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.

Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,³² 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.

At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.

Related resources

• Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
• Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
• Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Donepezil • Aricept
• Galantamine • Reminyl
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Valproate • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.

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

Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.

Three keys can help you safely treat dementia’s difficult behavioral and psychological symptoms:

• Differentiate medical from psychiatric causes of patients’ distress.
• Use antipsychotics and other drugs as adjuncts to psychosocial treatments.
• Start low and go slow when titrating dosages.

Although no treatment reverses the pathophysiology of progressive neurodegenerative disorders, managing agitation and other behaviors can alleviate patient suffering and reduce caregiver stress. Based on the evidence and our experience, this article describes a practical approach, including a treatment algorithm and evidence of atypical antipsychotics’ efficacy and side effects in this patient population.

Algorithm Treating behavioral symptoms in patients with dementia

Dementia’s behavioral symptoms

An International Psychogeriatric Association consensus statement¹ grouped dementia’s behavioral and psychological symptoms into two types:

• those usually assessed by interviewing patients and relatives—anxiety, depressed mood, hallucinations, and delusions
• those usually identified by observing patient behavior—aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviors, sexual disinhibition, hoarding, cursing, and shadowing.

These behaviors in community-living patients are distressing to family members and increase the risk for caregiver burnout—the most common reason for placing older patients in long-term care. In the nursing home, dementia’s symptoms reduce patients’ quality of life; interfere with feeding, bathing, and dressing; and—when violent—may endanger staff and other patients.

Rule out a medical cause

Differential diagnosis. Behavioral symptoms in dementia tend to be unpredictable, which makes diagnosis and treatment challenging. The first step is to determine if a medical or psychiatric condition might account for the behavior. For instance:

• A patient with dementia may be agitated because of a distended bladder or arthritis but unable to communicate his or her pain in words.
• In mild dementia, a pre-existing psychiatric disorder such as schizophrenia might be causing a patient’s hallucinations or delusions.
• Pacing and restlessness may be drug side effects and might be controlled by reducing dosages or switching to less-activating agents.

Delirium is also a risk for older patients—especially those with degenerative neurologic disorders. Common triggers in older patients include acute illness such as a urinary tract infection or pneumonia, alcohol or benzodiazepine withdrawal, anticholinergic agents, medication changes, and dehydration.

Delirium is characterized by acute onset and fluctuating neuropsychiatric symptoms, including disturbed consciousness and changes in attention and cognition. Taking a careful history to learn the course of treatment and the patient’s baseline cognitive function can help you differentiate dementia from delirium. Family members, physicians, and nursing staff are valuable sources of this information.

Use antipsychotics as adjuncts

Psychosocial interventions. After medical causes have been ruled out, consensus guidelines² recommend psychosocial interventions as first-line treatment of dementia’s behavioral symptoms (Algorithm). Suggested interventions for patients and caregivers are listed in Table 1.³

Antipsychotics. For patients who respond inadequately to psychosocial measures, the next step is to add an atypical antipsychotic. Because of side effects, conventional antipsychotics are not recommended for patients with dementia.

When prescribing atypicals, remember that older adults:

• are more sensitive to side effects than younger adults
• require lower starting and target dosages
• exhibit heterogeneity of response.

Older patients’ medical status can range from “fit” to “frail,” which influences individual response to medications. Generally, age-related changes in the way their bodies metabolize drugs account for older patients’ increased sensitivity to drug side effects (Box).^4-11

Atypical antipsychotics and dosages that have been shown benefit for managing behavioral symptoms in older patients with dementia include:

• risperidone, 0.5 to 1.5 mg/d¹²
• olanzapine, 5 to 10 mg/d¹³
• quetiapine, 25 to 350 mg/d¹⁴ (Table 2).^15,16

Start with low dosages, and titrate slowly. Increase once or twice a week until the lowest effective dosage is reached.

Augmenting agents. If antipsychotic monotherapy fails to achieve an adequate response or if side effects limit dosing, adjunctive agents may be added with caution. Augmenting agents that have shown benefit in some patients with dementia include:

• mood stabilizers such as divalproex¹⁷ or carbamazepine¹⁸
• cholinesterase inhibitors, such as donepezil, rivastigmine, or galantamine.¹⁹

Start divalproex at 125 mg bid or carbamazepine at 100 mg bid and titrate to effect. Concomitant carbamazepine will decrease blood levels of risperidone, olanzapine, and quetiapine because of hepatic enzyme induction.²⁰

Start donepezil at 5 mg once daily and increase after 4 to 6 weeks to 10 mg qd. When using rivastigmine, start with 1.5 mg bid and titrate to 9 to 12 mg/d in divided doses. Start galantamine at 4 mg bid and increase after 1 month to 8 mg bid.

Table 1

Suggested psychosocial interventions for older patients with dementia

Antipsychotic side effects

Atypical antipsychotics are more effective than conventional agents in treating negative symptoms and are associated with lower rates of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).²¹

Tardive dyskinesia. All antipsychotics can cause TD, although the risk is about 10 times greater with conventionals than atypicals. With conventionals, the annual cumulative TD incidence for young adults is 4 to 5%,²² and rates are much higher for middle-aged and older adults receiving chronic therapy:

• 29% after 1 year
• 50% after 2 years
• 63% after 3 years.²³

In older patients, use atypical rather than conventional antipsychotics to minimize TD risk. Observe carefully; if TD symptoms occur, cautiously withdraw the antipsychotic and consider trying another agent.

Other risks. Atypical antipsychotics may cause sedation, orthostatic hypotension (with an increased risk for falls), increased serum prolactin, and weight gain (Table 2).

Weight gain from atypical antipsychotics has been associated with adverse effects on glucose metabolism and increased risk for type 2 diabetes.²⁴ Some might argue that weight gain associated with olanzapine and other atypicals might benefit low-weight older patients. The frail elderly need to increase muscle mass, however, and the atypicals are associated with increases in fat mass.

Increased serum prolactin with risperidone theoretically could lead to loss of bone density, but evidence of this effect in older patients does not exist.

Start low, go slow

Clozapine may help control treatment-resistant psychosis in patients with schizophrenia and manage patients with severe TD.²⁵ However, clozapine’s increased risk of agranulocytosis, neurologic side effects (seizures, sedation, confusion), and anticholinergic effects limit its use in older patients, particularly those with neurodegenerative disorders (Table 2).

Dosing. In rare cases when using clozapine in older patients, start with 6.25 to 12.5 mg/d. Increase by 6.25 to 12.5 mg once or twice a week to 50 to 100 mg/d.

Risperidone has been used to treat agitation in older patients with dementia in two small studies:

In a 9-week, open-label trial, 15 patients (mean age 78) with dementia were given risperidone, 0.5 to 3 mg/d. Agitation improved significantly, as measured by the Cohen-Mansfield Agitation Inventory (CMAI)—a 29-item questionnaire completed by caregivers.²⁶ CMAI scores at study’s end averaged 49.5, compared with 70.5 at baseline.²⁷

A 12-week, placebo-controlled, doubleblind study examined risperidone—0.5, 1, or 2 mg/d—in 625 institutionalized patients (mean age 83) with dementia and agitation. Ninety-six patients had Functional Assessment Staging Rating Scale scores of 6A, indicating moderate to severe dementia. In patients receiving risperidone, these behavioral measures were significantly reduced:

• Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, which measure behavior severity
• BEHAVE-AD psychosis subscale scores
• BEHAVE-AD aggressiveness scores
• CMAI verbal and aggression scores.

Adverse effects were reported at 82% for all three risperidone dosages and 85% for placebo. Side effects including somnolence, EPS, and peripheral edema were dose-related.¹²

Another trial compared risperidone or haloperidol, 0.5 to 4 mg/d, with placebo in treating 344 patients with behavioral symptoms of dementia. After 12 weeks of risperidone, mean dosage 1.1 mg/d:

• mean total BEHAVE-AD score decreased by 53%, compared with 37% in the placebo group
• CMAI score decreased by 32%, compared with 18% in the placebo group.

EPS were more severe with haloperidol than with risperidone or placebo.²⁸

Risk of stroke. A small but significantly increased incidence of stroke and stroke-like events was recently reported in older patients with dementia when treated with risperidone. These events occurred in double-blind, placebocontrolled trials in patients (mean age 82) with Alzheimer’s, vascular, and mixed dementias.

Box

Most patients who experienced cerebrovascular events had one or more stroke risk factors, including diabetes, hypertension, atrial fibrillation, heart arrhythmia, atherosclerosis, or heart failure. They did not show a pattern of reduced blood pressure or orthostatic changes.^12,29

Table 2

Antipsychotic side effects and dosages in older patients with dementia*

Dosing. For older patients with dementia and psychosis, start risperidone at 0.25 to 0.5 mg/d and increase by no more than 0.25 to 0.5 mg once or twice per week. Do not exceed 3 mg/d. For agitation, a 1998 Expert Consensus Guideline Series panel² recommended starting risperidone at 0.25 to 0.5 mg/d and increasing to an average of 0.5 to 1.5 mg/d.

Olanzapine. Two double-blind, placebo-controlled studies have examined olanzapine in treating agitation associated with dementia.

Saterlee et al³⁰ compared olanzapine, mean 2.4 mg/d, with placebo in outpatients (mean age 79) with Alzheimer’s disease and psychosis. No significant differences were noted in hepatic transaminase levels, leukopenia, EPS, or orthostatic changes.

In a later study,¹³ nursing home patients (mean age 83) with Alzheimer’s disease, psychosis, and agitation were randomly assigned to receive olanzapine—5, 10, or 15 mg/d—or placebo. After 6 weeks, patients receiving olanzapine, 5 or 10 mg/d, showed significant improvement in Neuropsychiatric Inventory (NPI) total core scores. Olanzapine, 15 mg/d, was not significantly more effective than placebo.

Adverse events such as somnolence and abnormal gait occurred more often with olanzapine than placebo. The somnolence rate with olanzapine was 14% for 5 mg/d and 13% for 10 mg/d, compared with 3% for placebo. For abnormal gait, the rate with olanzapine was 11% for 5 mg/d and 7% for 10 mg/d, compared with 1% for placebo.

Dosing. Start olanzapine at 2.5 mg/d, and increase after 1 to 3 days to 5 mg/d. If symptoms are not adequately controlled, titrate by 2.5-mg increments to 10 mg/d.

Quetiapine. One open-label study¹⁴ examined using quetiapine in older patients with psychotic disorders. The study enrolled 184 patients (mean age 76) with Alzheimer’s disease, Parkinson’s disease, schizophrenia, vascular dementia, schizoaffective disorder, bipolar disorder, or major depression. Before the trial, patients were taking various conventional and atypical antipsychotics.

Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions (CGI) scores improved significantly after 52 weeks of quetiapine, median 137.5 mg/d. BPRS scores improved 20% in 49% of patients who completed the study.

Less than one-half (48%) of enrolled patients completed the study. Reasons for withdrawal included lack of efficacy (19%), adverse events or illness (15%; adverse events alone, 11%), lost to follow-up (13%), protocol noncompliance (3%), or diminished need for treatment (2%).

EPS occurred in 13% of patients. Mean total scores on the Simpson-Angus Rating Scale for Extrapyramidal Side Effects decreased 1.8 points, indicating reduced parkinsonian symptoms.

Dosing. Start quetiapine at 25 mg once at bedtime or bid; increase in 25-mg increments until the lowest effective dosage is achieved.

Ziprasidone. Little data exist on using ziprasidone in long-term care. In one recent study,³¹ ziprasidone (mean 100 mg/d) was given to 62 patients ages 64 to 92 with medical illnesses plus major depression, bipolar disorder, schizoaffective disorder, Alzheimer’s disease, or multi-infarct dementia. A retrospective chart review of 10 patients showed decreased agitation, as mean NPI scores declined from 76 to 33.

Sedation was the most common side effect. QTc findings, postural hypotension, and syncope rates did not change. Despite its limitations, this study suggests that ziprasidone is safe and effective in treating psychosis associated with dementia or other disorders.

Aripiprazole. As with ziprasidone, little data exist to guide the use of aripiprazole in older patients. In a randomized preliminary trial,³² 192 noninstitutionalized patients with Alzheimer’s disease and psychosis were treated for 10 weeks with aripiprazole, mean 10 mg/d, or placebo.

At 8 and 10 weeks, BPRS psychosis subscale scores improved significantly in patients taking aripiprazole, compared with placebo. EPS and akathisia improved, and somnolence was the most common side effect. Although this study enrolled noninstitutionalized patients with dementia, the results suggest that aripiprazole may help treat long-term care residents with neurodegenerative disorders and behavioral disturbances.

Related resources

• Zaraa AS. Dementia update: Pharmacologic management of agitation and psychosis in older demented patients. Geriatrics 2003;58(10):48-53.
• Mills EJ, Chow TW. Randomized controlled trials in long-term care of residents with dementia: a systematic review. J Am Med Dir Assoc 2003;4(6):302-7.
• Alzheimer’s Association. Treating agitation. www.alz.org/PhysCare/Treating/agitation.htm

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Donepezil • Aricept
• Galantamine • Reminyl
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Rivastigmine • Exelon
• Valproate • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Kasckow receives research support from, is a consultant to, or is a speaker for Eli Lilly & Co., Forest Laboratories, Solvay Pharmaceuticals, AstraZeneca Pharmaceuticals, Organon, Janssen Pharmaceutica, and Pfizer Inc.

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

Dr. Mohamed receives research support form Forest Laboratories and is a speaker for Eli Lilly & Co.

History: Terrors at age 8

Ms. J, age 35, began having sleepwalking episodes at age 8. At times they involved odd behaviors, such as carrying her brother’s shirt into the bathroom, placing it into the sink, and turning on the water.

As a child, Ms. J also began experiencing nocturnal awakenings characterized by panic and shouting. She sometimes saw a frightening image, usually of something falling on her. She would promptly return to sleep after each incident and had trouble remembering the event the next morning. The sleepwalking and awakening occurred monthly—more often when she was under stress or fatigued—until her early 20s.

At age 21, Ms. J. was under severe stress while preparing for a crucial graduate school examination and was losing much sleep. At this point, the episodes began to occur once or twice nightly.

She consulted a sleep specialist. EEG results were normal, but a sleep study was not helpful because she experienced no events that night. The specialist diagnosed Ms. J as having night terrors and prescribed clonazepam, 0.5 mg nightly. The agent did not prevent the events, but their frequency returned to baseline after Ms. J took her exam.

Were Ms. J’s clinical presentation and course consistent with night terrors? How would you treat her symptoms at this point?

The authors’ observations

Night terrors are an arousal disorder that usually begins in early childhood and affects 1% to 4% of the population.¹ The disorder usually disappears before puberty.

Episodes of this parasomnia typically occur one to four times each month and can last several minutes. They are characterized by sudden awakenings with panic, disorientation, vocalization, and autonomic discharge. Patients sometimes see a frightening image. The events occur in stage 4 sleep, usually soon after falling asleep. Disorientation and a prompt return to sleep may follow.² Sleeptalking and sleepwalking may also be present. The patient often cannot remember the event the next morning.

At this point, night terrors are a reasonable explanation for Ms. J’s nocturnal phenomena. Benzodiazepines, especially clonazepam, have been shown to decrease night terror frequency.³

Continued history: A new mother’s stress

At age 34, Ms. J gave birth to her first child. Weeks later, the nocturnal events began to occur at least three times nightly—every hour on some nights. Because their frequency disrupted her sleep, Ms. J constantly felt tired. Stress, emotional upset, and sleep deprivation exacerbated the events, which were stereotypical and included:

• sudden jerking of the right upper and/or lower extremities
• sudden sitting up and posing with the right arm flexed and internally rotated
• hallucinations of spiders or people
• sudden body flexion accompanied by an “electric shock” sensation in the head
• sitting up in bed, touching and picking at the sheets
• nonsensical speech after sitting up in bed
• sudden fear that Ms. J’s baby was hurt or dead, accompanied by searching the bed and under the pillow for the baby
• episodes of panic often accompanied by crying out, jumping out of bed and—in some cases—running.

Several times she ran down the stairs and out of the house while asleep. During one event, she jumped out of bed and fractured her foot. In another, she jumped from the bed and ran headfirst into a wall, causing bruising but no severe injury.

Each event was accompanied by confusion for 10 seconds to 3 minutes. Ms. J remembered about one-half the events; her husband described the remainder. She invariably returned to sleep immediately after each event.

A second sleep specialist diagnosed Ms. J as having night terrors. Unsatisfied with the diagnosis, she consulted a neurologist who specialized in epilepsy. The neurologist diagnosed her as having nocturnal frontal lobe epilepsy (NFLE) based on her history. A video EEG study—which showed spike and wave activity in the left frontal lobe during the nocturnal events—confirmed the diagnosis. The events all occurred during stage 2 sleep.

Is Ms. J’s latest diagnosis on target? Which clinical features in her case would differentiate sleep epilepsy from parasomnias?

The authors’ observations

Frontal lobe epilepsy can take many forms. Seizures can occur during sleep and/or while awake and consist of sudden, brief (<1 minute) motor attacks occurring in clusters. The prevalence of sleep epilepsy among persons with seizure disorders has been estimated at 7.5% to 45%, based on studies of small patient populations.⁴

Nocturnal frontal lobe seizures:

• occur only in non-REM (usually stage 2) sleep.
• can occur at any time of night
• usually begin in middle childhood to early adolescence, but onset in early childhood or adulthood has been reported.⁵ Seizures usually subside during adulthood (Table).⁶

Table

Characteristics of parasomnias and nocturnal epilepsy

These seizures are clinically polymorphous but stereotypical in each patient. Seizure type varies depending on which frontal lobe region is affected.

Nocturnal seizures universally have an explosive onset, with motor symptoms such as jerking, rocking, pelvic thrusting, tonic posturing, kicking, scrambling about, and touching the bed with one’s hand. Other possible occurrences include:

• sensory phenomena such as illusions and hallucinations, sensations of buzzing, vibration, and olfactory or gustatory sensations
• aphasia or other vocal events, such as laughing, screaming, or making odd noises
• fear and autonomic discharge simulating a night terror or panic attack.⁷

Confusion also is possible, although consciousness many times is preserved through the episode.

As with other seizures, sleep disruption exacerbates NFLE. Most patients have a normal interictal EEG.

Because NFLE is often misdiagnosed as a parasomnia, the psychiatrist needs to consider this disorder in the differential diagnosis. Any patient with a suspected parasomnia should be evaluated by a neurologist for NFLE if:

• the nocturnal events have not ceased by young adulthood
• events consist of prominent stereotypical motor symptoms that occur in clusters and/or have caused physical injury.

Extended history: Family stories

Ms. J’s neurologist asked whether any relatives have experienced similar nocturnal events.

Upon talking with family members, she learned that her aunt (her father’s sister) experienced nocturnal hallucinations and panic episodes well into her 50s. Her first cousin (her aunt’s daughter) also has nocturnal hallucinations and panic episodes and runs in her sleep. Two of her father’s cousins—twin brothers—were also affected. One of the brothers experienced explosive episodes, sometimes assaulting the other brother while asleep; he once had to be restrained from jumping out a window.

Other family members or surviving spouses described similar events that are clinically consistent with frontal lobe seizures. Interestingly, tic disorders run in the same branches of the family as the seizures.

Ms. J was diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) based on her diagnosis of NFLE and family history of similar events.

The authors’ observations

ADNFLE is an inherited disorder that displays 70% penetrance.⁸ Families in Australia, Canada, Spain, Japan, Korea, Germany, Great Britain, Italy, and Norway have been described with the disorder. No accurate prevalence data exist.⁹

Ms. J’s family traces its roots to Lithuania and White Russia (now Belarus) and is Ashkenazi Jewish. No literature describes the disorder in this population or these locations.

ADNFLE was the first genetic epilepsy to be associated with a defect in a single gene. It was recognized as a disorder in 1994, having previously been described with different names by multiple authors.

The disorderis a “channelopathy,” signifying a defective ion channel resulting in abnormal neuronal cell membrane conduction. The affected gene is the acetylcholine receptor, which is widely distributed in the brain. Missense mutations of the receptor gene lead to a change in an amino acid found in the center of the receptor pore. Ordinarily, the centers of ion channel pores are lined with hydrophobic amino acids to facilitate entrance of ions. The mutations in affected individuals result in a hydrophobic amino acid substitution. Different families display different mutations of the gene.¹⁰

In ADNFLE, there is mutation in the second transmembrane region of the alpha-4 subunit of the neuronal acetylcholine receptor. Defective receptors result in reduced channel permeability to calcium, causing fast desensitization and receptor hypoactivity. This has been postulated to cause an imbalance in excitatory/inhibitory synaptic transmission.¹¹ Further study will elucidate the acetylcholine receptor’s relationship to brain functioning.

Treatment: Medication trial

Lamotrigine was started at 25 mg/d and titrated upward by 25 to 50 mg per week. When the dosage reached 500 mg/d, seizure frequency was reduced to once weekly.

Because Ms. J’s seizures were associated with stress and fatigue, she reduced her work hours and modified her job duties. Alcohol increased the frequency of the seizures, so she abstained from alcohol consumption. She also adhered to a consistent bedtime and slept at least 8 hours every night. After making these lifestyle modifications, Ms. J’s seizers decreased to once per month.

Why was lamotrigine chosen for Ms. J? What other drug options exist to treat sleep epilepsy?

The authors’ observations

Many clinicians consider carbamazepine the drug of choice for NFLE. Because NFLE is an epilepsy of partial onset, however, medications used to treat partial-onset epilepsy—including lamotrigine, topiramate, oxcarbazepine, gabapentin, and levetiracetam—are presumed to work as well. Because lamotrigine is considered the safest antiepileptic in pregnancy, the neurologist chose this agent for Ms. J.

Although comparative studies of antiepileptics for partial epilepsies have shown no difference in efficacy,^12,13 no comparative studies of antiepileptics in NFLE have been published.

Related resources

• Hales RE, Yudofsky SC (eds). Textbook of neuropsychiatry (3rd ed). Washington, DC: American PsychiatricPublishing,1997. Specific chapters:
• Adams JM, Berkovic SF, Scheffer IE. Autosomal dominant nocturnal frontal lobe epilepsy. Gene Reviews. Available at: http://www.geneclinics.org/profiles/adnfle/. Accessed Dec. 22, 2003.

Drug brand names

• Carbamazepine • Tegretol
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Oxcarbazepine • Trileptal
• Topiramate • Topamax

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

History: Terrors at age 8

Ms. J, age 35, began having sleepwalking episodes at age 8. At times they involved odd behaviors, such as carrying her brother’s shirt into the bathroom, placing it into the sink, and turning on the water.

As a child, Ms. J also began experiencing nocturnal awakenings characterized by panic and shouting. She sometimes saw a frightening image, usually of something falling on her. She would promptly return to sleep after each incident and had trouble remembering the event the next morning. The sleepwalking and awakening occurred monthly—more often when she was under stress or fatigued—until her early 20s.

At age 21, Ms. J. was under severe stress while preparing for a crucial graduate school examination and was losing much sleep. At this point, the episodes began to occur once or twice nightly.

She consulted a sleep specialist. EEG results were normal, but a sleep study was not helpful because she experienced no events that night. The specialist diagnosed Ms. J as having night terrors and prescribed clonazepam, 0.5 mg nightly. The agent did not prevent the events, but their frequency returned to baseline after Ms. J took her exam.

Were Ms. J’s clinical presentation and course consistent with night terrors? How would you treat her symptoms at this point?

The authors’ observations

Night terrors are an arousal disorder that usually begins in early childhood and affects 1% to 4% of the population.¹ The disorder usually disappears before puberty.

Episodes of this parasomnia typically occur one to four times each month and can last several minutes. They are characterized by sudden awakenings with panic, disorientation, vocalization, and autonomic discharge. Patients sometimes see a frightening image. The events occur in stage 4 sleep, usually soon after falling asleep. Disorientation and a prompt return to sleep may follow.² Sleeptalking and sleepwalking may also be present. The patient often cannot remember the event the next morning.

At this point, night terrors are a reasonable explanation for Ms. J’s nocturnal phenomena. Benzodiazepines, especially clonazepam, have been shown to decrease night terror frequency.³

Continued history: A new mother’s stress

At age 34, Ms. J gave birth to her first child. Weeks later, the nocturnal events began to occur at least three times nightly—every hour on some nights. Because their frequency disrupted her sleep, Ms. J constantly felt tired. Stress, emotional upset, and sleep deprivation exacerbated the events, which were stereotypical and included:

• sudden jerking of the right upper and/or lower extremities
• sudden sitting up and posing with the right arm flexed and internally rotated
• hallucinations of spiders or people
• sudden body flexion accompanied by an “electric shock” sensation in the head
• sitting up in bed, touching and picking at the sheets
• nonsensical speech after sitting up in bed
• sudden fear that Ms. J’s baby was hurt or dead, accompanied by searching the bed and under the pillow for the baby
• episodes of panic often accompanied by crying out, jumping out of bed and—in some cases—running.

Several times she ran down the stairs and out of the house while asleep. During one event, she jumped out of bed and fractured her foot. In another, she jumped from the bed and ran headfirst into a wall, causing bruising but no severe injury.

Each event was accompanied by confusion for 10 seconds to 3 minutes. Ms. J remembered about one-half the events; her husband described the remainder. She invariably returned to sleep immediately after each event.

A second sleep specialist diagnosed Ms. J as having night terrors. Unsatisfied with the diagnosis, she consulted a neurologist who specialized in epilepsy. The neurologist diagnosed her as having nocturnal frontal lobe epilepsy (NFLE) based on her history. A video EEG study—which showed spike and wave activity in the left frontal lobe during the nocturnal events—confirmed the diagnosis. The events all occurred during stage 2 sleep.

Is Ms. J’s latest diagnosis on target? Which clinical features in her case would differentiate sleep epilepsy from parasomnias?

The authors’ observations

Frontal lobe epilepsy can take many forms. Seizures can occur during sleep and/or while awake and consist of sudden, brief (<1 minute) motor attacks occurring in clusters. The prevalence of sleep epilepsy among persons with seizure disorders has been estimated at 7.5% to 45%, based on studies of small patient populations.⁴

Nocturnal frontal lobe seizures:

• occur only in non-REM (usually stage 2) sleep.
• can occur at any time of night
• usually begin in middle childhood to early adolescence, but onset in early childhood or adulthood has been reported.⁵ Seizures usually subside during adulthood (Table).⁶

Table

Characteristics of parasomnias and nocturnal epilepsy

These seizures are clinically polymorphous but stereotypical in each patient. Seizure type varies depending on which frontal lobe region is affected.

Nocturnal seizures universally have an explosive onset, with motor symptoms such as jerking, rocking, pelvic thrusting, tonic posturing, kicking, scrambling about, and touching the bed with one’s hand. Other possible occurrences include:

• sensory phenomena such as illusions and hallucinations, sensations of buzzing, vibration, and olfactory or gustatory sensations
• aphasia or other vocal events, such as laughing, screaming, or making odd noises
• fear and autonomic discharge simulating a night terror or panic attack.⁷

Confusion also is possible, although consciousness many times is preserved through the episode.

As with other seizures, sleep disruption exacerbates NFLE. Most patients have a normal interictal EEG.

Because NFLE is often misdiagnosed as a parasomnia, the psychiatrist needs to consider this disorder in the differential diagnosis. Any patient with a suspected parasomnia should be evaluated by a neurologist for NFLE if:

• the nocturnal events have not ceased by young adulthood
• events consist of prominent stereotypical motor symptoms that occur in clusters and/or have caused physical injury.

Extended history: Family stories

Ms. J’s neurologist asked whether any relatives have experienced similar nocturnal events.

Upon talking with family members, she learned that her aunt (her father’s sister) experienced nocturnal hallucinations and panic episodes well into her 50s. Her first cousin (her aunt’s daughter) also has nocturnal hallucinations and panic episodes and runs in her sleep. Two of her father’s cousins—twin brothers—were also affected. One of the brothers experienced explosive episodes, sometimes assaulting the other brother while asleep; he once had to be restrained from jumping out a window.

Other family members or surviving spouses described similar events that are clinically consistent with frontal lobe seizures. Interestingly, tic disorders run in the same branches of the family as the seizures.

Ms. J was diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) based on her diagnosis of NFLE and family history of similar events.

The authors’ observations

ADNFLE is an inherited disorder that displays 70% penetrance.⁸ Families in Australia, Canada, Spain, Japan, Korea, Germany, Great Britain, Italy, and Norway have been described with the disorder. No accurate prevalence data exist.⁹

Ms. J’s family traces its roots to Lithuania and White Russia (now Belarus) and is Ashkenazi Jewish. No literature describes the disorder in this population or these locations.

ADNFLE was the first genetic epilepsy to be associated with a defect in a single gene. It was recognized as a disorder in 1994, having previously been described with different names by multiple authors.

The disorderis a “channelopathy,” signifying a defective ion channel resulting in abnormal neuronal cell membrane conduction. The affected gene is the acetylcholine receptor, which is widely distributed in the brain. Missense mutations of the receptor gene lead to a change in an amino acid found in the center of the receptor pore. Ordinarily, the centers of ion channel pores are lined with hydrophobic amino acids to facilitate entrance of ions. The mutations in affected individuals result in a hydrophobic amino acid substitution. Different families display different mutations of the gene.¹⁰

In ADNFLE, there is mutation in the second transmembrane region of the alpha-4 subunit of the neuronal acetylcholine receptor. Defective receptors result in reduced channel permeability to calcium, causing fast desensitization and receptor hypoactivity. This has been postulated to cause an imbalance in excitatory/inhibitory synaptic transmission.¹¹ Further study will elucidate the acetylcholine receptor’s relationship to brain functioning.

Treatment: Medication trial

Lamotrigine was started at 25 mg/d and titrated upward by 25 to 50 mg per week. When the dosage reached 500 mg/d, seizure frequency was reduced to once weekly.

Because Ms. J’s seizures were associated with stress and fatigue, she reduced her work hours and modified her job duties. Alcohol increased the frequency of the seizures, so she abstained from alcohol consumption. She also adhered to a consistent bedtime and slept at least 8 hours every night. After making these lifestyle modifications, Ms. J’s seizers decreased to once per month.

Why was lamotrigine chosen for Ms. J? What other drug options exist to treat sleep epilepsy?

The authors’ observations

Many clinicians consider carbamazepine the drug of choice for NFLE. Because NFLE is an epilepsy of partial onset, however, medications used to treat partial-onset epilepsy—including lamotrigine, topiramate, oxcarbazepine, gabapentin, and levetiracetam—are presumed to work as well. Because lamotrigine is considered the safest antiepileptic in pregnancy, the neurologist chose this agent for Ms. J.

Although comparative studies of antiepileptics for partial epilepsies have shown no difference in efficacy,^12,13 no comparative studies of antiepileptics in NFLE have been published.

Related resources

• Hales RE, Yudofsky SC (eds). Textbook of neuropsychiatry (3rd ed). Washington, DC: American PsychiatricPublishing,1997. Specific chapters:
• Adams JM, Berkovic SF, Scheffer IE. Autosomal dominant nocturnal frontal lobe epilepsy. Gene Reviews. Available at: http://www.geneclinics.org/profiles/adnfle/. Accessed Dec. 22, 2003.

Drug brand names

• Carbamazepine • Tegretol
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Oxcarbazepine • Trileptal
• Topiramate • Topamax

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

History: Terrors at age 8

Ms. J, age 35, began having sleepwalking episodes at age 8. At times they involved odd behaviors, such as carrying her brother’s shirt into the bathroom, placing it into the sink, and turning on the water.

As a child, Ms. J also began experiencing nocturnal awakenings characterized by panic and shouting. She sometimes saw a frightening image, usually of something falling on her. She would promptly return to sleep after each incident and had trouble remembering the event the next morning. The sleepwalking and awakening occurred monthly—more often when she was under stress or fatigued—until her early 20s.

At age 21, Ms. J. was under severe stress while preparing for a crucial graduate school examination and was losing much sleep. At this point, the episodes began to occur once or twice nightly.

She consulted a sleep specialist. EEG results were normal, but a sleep study was not helpful because she experienced no events that night. The specialist diagnosed Ms. J as having night terrors and prescribed clonazepam, 0.5 mg nightly. The agent did not prevent the events, but their frequency returned to baseline after Ms. J took her exam.

Were Ms. J’s clinical presentation and course consistent with night terrors? How would you treat her symptoms at this point?

The authors’ observations

Night terrors are an arousal disorder that usually begins in early childhood and affects 1% to 4% of the population.¹ The disorder usually disappears before puberty.

Episodes of this parasomnia typically occur one to four times each month and can last several minutes. They are characterized by sudden awakenings with panic, disorientation, vocalization, and autonomic discharge. Patients sometimes see a frightening image. The events occur in stage 4 sleep, usually soon after falling asleep. Disorientation and a prompt return to sleep may follow.² Sleeptalking and sleepwalking may also be present. The patient often cannot remember the event the next morning.

At this point, night terrors are a reasonable explanation for Ms. J’s nocturnal phenomena. Benzodiazepines, especially clonazepam, have been shown to decrease night terror frequency.³

Continued history: A new mother’s stress

At age 34, Ms. J gave birth to her first child. Weeks later, the nocturnal events began to occur at least three times nightly—every hour on some nights. Because their frequency disrupted her sleep, Ms. J constantly felt tired. Stress, emotional upset, and sleep deprivation exacerbated the events, which were stereotypical and included:

• sudden jerking of the right upper and/or lower extremities
• sudden sitting up and posing with the right arm flexed and internally rotated
• hallucinations of spiders or people
• sudden body flexion accompanied by an “electric shock” sensation in the head
• sitting up in bed, touching and picking at the sheets
• nonsensical speech after sitting up in bed
• sudden fear that Ms. J’s baby was hurt or dead, accompanied by searching the bed and under the pillow for the baby
• episodes of panic often accompanied by crying out, jumping out of bed and—in some cases—running.

Several times she ran down the stairs and out of the house while asleep. During one event, she jumped out of bed and fractured her foot. In another, she jumped from the bed and ran headfirst into a wall, causing bruising but no severe injury.

Each event was accompanied by confusion for 10 seconds to 3 minutes. Ms. J remembered about one-half the events; her husband described the remainder. She invariably returned to sleep immediately after each event.

A second sleep specialist diagnosed Ms. J as having night terrors. Unsatisfied with the diagnosis, she consulted a neurologist who specialized in epilepsy. The neurologist diagnosed her as having nocturnal frontal lobe epilepsy (NFLE) based on her history. A video EEG study—which showed spike and wave activity in the left frontal lobe during the nocturnal events—confirmed the diagnosis. The events all occurred during stage 2 sleep.

Is Ms. J’s latest diagnosis on target? Which clinical features in her case would differentiate sleep epilepsy from parasomnias?

The authors’ observations

Frontal lobe epilepsy can take many forms. Seizures can occur during sleep and/or while awake and consist of sudden, brief (<1 minute) motor attacks occurring in clusters. The prevalence of sleep epilepsy among persons with seizure disorders has been estimated at 7.5% to 45%, based on studies of small patient populations.⁴

Nocturnal frontal lobe seizures:

• occur only in non-REM (usually stage 2) sleep.
• can occur at any time of night
• usually begin in middle childhood to early adolescence, but onset in early childhood or adulthood has been reported.⁵ Seizures usually subside during adulthood (Table).⁶

Table

Characteristics of parasomnias and nocturnal epilepsy

These seizures are clinically polymorphous but stereotypical in each patient. Seizure type varies depending on which frontal lobe region is affected.

Nocturnal seizures universally have an explosive onset, with motor symptoms such as jerking, rocking, pelvic thrusting, tonic posturing, kicking, scrambling about, and touching the bed with one’s hand. Other possible occurrences include:

• sensory phenomena such as illusions and hallucinations, sensations of buzzing, vibration, and olfactory or gustatory sensations
• aphasia or other vocal events, such as laughing, screaming, or making odd noises
• fear and autonomic discharge simulating a night terror or panic attack.⁷

Confusion also is possible, although consciousness many times is preserved through the episode.

As with other seizures, sleep disruption exacerbates NFLE. Most patients have a normal interictal EEG.

Because NFLE is often misdiagnosed as a parasomnia, the psychiatrist needs to consider this disorder in the differential diagnosis. Any patient with a suspected parasomnia should be evaluated by a neurologist for NFLE if:

• the nocturnal events have not ceased by young adulthood
• events consist of prominent stereotypical motor symptoms that occur in clusters and/or have caused physical injury.

Extended history: Family stories

Ms. J’s neurologist asked whether any relatives have experienced similar nocturnal events.

Upon talking with family members, she learned that her aunt (her father’s sister) experienced nocturnal hallucinations and panic episodes well into her 50s. Her first cousin (her aunt’s daughter) also has nocturnal hallucinations and panic episodes and runs in her sleep. Two of her father’s cousins—twin brothers—were also affected. One of the brothers experienced explosive episodes, sometimes assaulting the other brother while asleep; he once had to be restrained from jumping out a window.

Other family members or surviving spouses described similar events that are clinically consistent with frontal lobe seizures. Interestingly, tic disorders run in the same branches of the family as the seizures.

Ms. J was diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) based on her diagnosis of NFLE and family history of similar events.

The authors’ observations

ADNFLE is an inherited disorder that displays 70% penetrance.⁸ Families in Australia, Canada, Spain, Japan, Korea, Germany, Great Britain, Italy, and Norway have been described with the disorder. No accurate prevalence data exist.⁹

Ms. J’s family traces its roots to Lithuania and White Russia (now Belarus) and is Ashkenazi Jewish. No literature describes the disorder in this population or these locations.

ADNFLE was the first genetic epilepsy to be associated with a defect in a single gene. It was recognized as a disorder in 1994, having previously been described with different names by multiple authors.

The disorderis a “channelopathy,” signifying a defective ion channel resulting in abnormal neuronal cell membrane conduction. The affected gene is the acetylcholine receptor, which is widely distributed in the brain. Missense mutations of the receptor gene lead to a change in an amino acid found in the center of the receptor pore. Ordinarily, the centers of ion channel pores are lined with hydrophobic amino acids to facilitate entrance of ions. The mutations in affected individuals result in a hydrophobic amino acid substitution. Different families display different mutations of the gene.¹⁰

In ADNFLE, there is mutation in the second transmembrane region of the alpha-4 subunit of the neuronal acetylcholine receptor. Defective receptors result in reduced channel permeability to calcium, causing fast desensitization and receptor hypoactivity. This has been postulated to cause an imbalance in excitatory/inhibitory synaptic transmission.¹¹ Further study will elucidate the acetylcholine receptor’s relationship to brain functioning.

Treatment: Medication trial

Lamotrigine was started at 25 mg/d and titrated upward by 25 to 50 mg per week. When the dosage reached 500 mg/d, seizure frequency was reduced to once weekly.

Because Ms. J’s seizures were associated with stress and fatigue, she reduced her work hours and modified her job duties. Alcohol increased the frequency of the seizures, so she abstained from alcohol consumption. She also adhered to a consistent bedtime and slept at least 8 hours every night. After making these lifestyle modifications, Ms. J’s seizers decreased to once per month.

Why was lamotrigine chosen for Ms. J? What other drug options exist to treat sleep epilepsy?

The authors’ observations

Many clinicians consider carbamazepine the drug of choice for NFLE. Because NFLE is an epilepsy of partial onset, however, medications used to treat partial-onset epilepsy—including lamotrigine, topiramate, oxcarbazepine, gabapentin, and levetiracetam—are presumed to work as well. Because lamotrigine is considered the safest antiepileptic in pregnancy, the neurologist chose this agent for Ms. J.

Although comparative studies of antiepileptics for partial epilepsies have shown no difference in efficacy,^12,13 no comparative studies of antiepileptics in NFLE have been published.

Related resources

• Hales RE, Yudofsky SC (eds). Textbook of neuropsychiatry (3rd ed). Washington, DC: American PsychiatricPublishing,1997. Specific chapters:
• Adams JM, Berkovic SF, Scheffer IE. Autosomal dominant nocturnal frontal lobe epilepsy. Gene Reviews. Available at: http://www.geneclinics.org/profiles/adnfle/. Accessed Dec. 22, 2003.

Drug brand names

• Carbamazepine • Tegretol
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Oxcarbazepine • Trileptal
• Topiramate • Topamax

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.