Evidence-Based Reviews

Discuss this article

Sammy, age 7, is referred to you by his pediatrician because of a 4-week history of frequent eye blinking. His parents say he blinks a lot when bored but very little when playing baseball. They recall that he also has intermittently sniffed and nodded his head over the last 12 months. Neither Sammy nor his friends seem to be bothered by the blinking. Except for the tics, Sammy’s physical and mental status exams are normal.

Since preschool, Sammy’s teachers have complained that his backpack and desk are always a mess. Sammy is well-meaning but forgetful in his chores at home. A paternal uncle has head-turning movements, counts his steps, and becomes distressed if books on his shelf are not in alphabetical order.

Tics, such as strong eye blinks or repetitive shoulder shrugs, can distress a child or his/her parents, but the conditions associated with tic disorders often are more problematic than the tic disorder itself. High rates of comorbid conditions are recognized in persons with Tourette syndrome, including:

• obsessive-compulsive disorder (OCD) in >80%¹
• attention-deficit/hyperactivity disorder (ADHD) in ≤70%²
• anxiety disorders in 30%³
• rage, aggression, learning disabilities, and autism less commonly.

The strategy we recommend for managing tic disorders includes assessing tic severity, educating the family about the illness, determining whether a comorbid condition is present, and managing these conditions appropriately. Above all, we emphasize a risk-benefit analysis guided by the Hippocratic principle of “do no harm.”

Characteristics of tic disorders

You diagnose Sammy with Tourette syndrome because he meets DSM-IV-TR criteria of at least 2 motor tics and 1 vocal tic that have persisted for 1 year without more than a 3-month hiatus, with tic onset before age 18. Because tics may resemble other movement disorders, you rule out stereotypies, dystonia, chorea, ballism, and myoclonus (Table 1). You explain to his parents that Sammy’s condition is a heritable, neurobehavioral disorder that typically begins in childhood and is associated in families with OCD, ADHD, and autism spectrum disorders.

His parents ask about the difference between tics and other movements. You explain that eye-blinking tics—like other motor tics—appear as sudden, repetitive, stereotyped, nonrhythmic movements that involve discrete muscle groups. (View a video of a patient with tics.) Simple motor tics are focal movements involving 1 group of muscles, whereas complex tics are sequential patterns of movement that involve >1 muscle group or resemble purposeful movements (Table 2).

Table 1

Features of 5 movement disorders that may resemble tics

Table 2

Characteristics of simple and complex motor and vocal tics*

Older children frequently describe a premonitory urge prior to the tic. Patients typically can suppress tics for a transient period of time, although during tic suppression they usually feel restless and anticipate performing their tic. The ultimate performance of the tic brings relief. Tic suppression also occurs during focused activity. Emotional stress, fatigue, illness, or boredom can exacerbate tics.

To begin monitoring Sammy’s clinical course, you administer 3 assessment tools described inTable 3. You explain to Sammy’s parents that these tests will be repeated yearly or when tics worsen. However, you tell his parents that these scores alone will not determine present or future clinical decisions, including treatments. You also recommend that they connect with support groups on the Tourette Syndrome Association (TSA) Web site.

CASE CONTINUED: Changes over time

Sammy’s parents appreciate your explanation and say they will share information from the TSA Web site with Sammy’s principal, teachers, and classmates. The family agrees to return in 6 months or sooner if the tics worsen.

By age 8, Sammy develops multiple tics: facial grimacing, looking upwards, punching movements, whistling, and throat clearing. He is slightly bothered by these tics, and his friends have asked him about them. He tells them he has Tourette syndrome, and that usually ends the questioning. He returns for a follow-up visit because his parents notice a dramatic increase in his tics after Sammy’s father loses his job.

Treatment options

When deciding to treat a child’s tics, the first step is to determine whether to pursue a nonpharmacologic or pharmacologic approach (Algorithm). To tailor an approach most suited for an individual child, discuss with the family their feelings about therapy and medications. This information—along with tic severity—will help determine a treatment plan.

Behavior therapy and medication are management strategies; neither can cure a tic disorder. The most conservative approach to tic treatment is to:

• provide the child and family with basic guidelines for managing tics
• help alleviate environmental stress and other potential triggers.

Algorithm: Recommended treatment of tics in children and adolescents

CASE CONTINUED: A first intervention

You discuss treatment options with Sammy’s family, and they view medication as a last resort. Sammy does not seem to be bothered by his tics, and his parents do not wish to start him on daily medications. Given this situation, habit reversal therapy (HRT) is appropriate for Sammy because he is old enough to participate in HRT to reduce his tics.

HRT is an effective nonpharmacologic approach to help children with tics.⁴ Its 3 components are:

• awareness training
• competing response training
• social support.⁵

This simplified version of the original HRT can be completed in eight 1-hour sessions. Good candidates are patients who are cognitively mature enough to understand the therapy’s goals and compliant with frequent clinic visits. They also must practice the strategies at home.

It should not be difficult for psychiatrists to learn HRT—or refer to therapists who are willing to learn it—with the available instructional manual.

CASE CONTINUED: Practicing alternatives

You ask Sammy to imitate his tics. After helping him become more aware of his tics, you encourage him to develop a more socially appropriate movement to engage in whenever he feels the urge to punch. Sammy chooses to clench his fist in his pocket. He also learns to breathe in whenever he has an urge to whistle. you advise Sammy’s parents to reward his efforts to suppress the tics. He practices the strategies daily.

At age 12, Sammy returns to your office. He has begun to have frequent neck-jerking tics, which cause neck pain and daily headaches. He also is slapping his thigh and having frequent vocal tics characterized by loud shrieking. The vocal tics are disruptive in class, even though Sammy sits toward the back of the room. Sammy’s classmates tease him, and he is very frustrated.

Medication approach

The decision to start a medication for tics is complex. Scores from the YGTSS, PUTS, and GTS-QOL scales (Table 3) provide only a partial clinical picture. This decision should be reached after a detailed discussion with the family about benefits and risks of medications and ensuring that everyone’s expectations are reasonable.

A variety of medications are available to treat patients with tics (Table 4). No medication can completely eliminate tics, however, and many have substantial side effects. Before initiating medical treatment, consider 3 questions:

• Is moderate or severe pain involved?
• Is there significant functional interference?
• Is there significant social disruption despite efforts to optimize the social environment for the child?

Sammy’s frequent neck-jerking tics now cause chronic daily headaches, and his shrieking vocal tics are interfering with classroom activities, so we recommended a 3-month trial of guanfacine following the dosing schedule in Table 4.

Table 3

3 scales for assessing tic severity and impact on functioning

Table 4

Medications with evidence of tic-suppressing effects*

The first-line pharmacologic agent for tic suppression generally is an alpha-adrenergic medication, unless the tics are severe.⁶

Clonidine and guanfacine usually are started at low doses and increased gradually. Although not as effective as neuroleptics, alpha-adrenergics have a lower potential for side effects and are easier to use because no laboratory tests need to be monitored. Adverse effects associated with alpha-adrenergic medications include sedation, dry mouth, dizziness, headache, and rebound hypertension if discontinued abruptly.

If tics are causing pain, some clinicians prefer conservative measures such as heat or ice, massage, analgesics, relaxation therapy, and reassurance.

Second-line agents include typical and atypical antipsychotics. Haloperidol and pimozide have shown efficacy in reducing tics in placebo- controlled studies,^7,8 as have risperidone (in 4 randomized controlled trials [RCTs]) and ziprasidone (in 1 RCT).^9,10 The emergence of serious side effects is a risk for both typical and atypical antipsychotics (Table 5).

Table 5

Potential adverse effects of antipsychotic treatment in children*

As part of your informed consent discussion, weigh the risk of side effects against the benefits of treatment. Point out to patients and their families that they can expect to see a decrease in tic frequency, but symptoms will not necessarily disappear with any medication. We tell our patients that with antipsychotics the best we can hope for is to reduce tic frequency by approximately one-half.⁶

When treating tics, start with 1 medication. However, if the tics are severe enough to require more than 1 medication, check for drug interactions.

Third-line agents. Agents that have not been tested in placebo-controlled trials can be considered third line; these are listed as category C (supported by open-label studies) in Table 4. Botulinum toxin injection has been found to be effective for motor and vocal tics.^11,12 Botulinum toxin and implantation of deep brain stimulators¹³ are invasive options and generally are reserved for severe, treatment-resistant tics.

CASE CONTINUED: Managing antipsychotics

After trying guanfacine for 12 weeks, Sammy notices no tic reduction. His parents consent to a low dose of risperidone. you review with them the American Psychiatric Association (APA)/American Diabetes Association (ADA) guidelines¹⁴ for managing metabolic problems in patients treated with atypical antipsychotics.

As instructed in the APA/ADA guidelines, obtain baseline measurements and monitor for metabolic effects of antipsychotic therapy over time (Table 6). Sammy starts risperidone at 0.5 mg once daily. After 2 weeks, he notices a decrease in his tics. At the 3-month visit after starting risperidone, he is happy with his risperidone dose and does not want to increase it. He has gained 3 pounds, and you instruct him to eat a well-balanced diet and exercise routinely. At the 6-month visit, his tics are minimal and his weight has stabilized.

Table 6

Children receiving antipsychotics: monitoring recommendations

You recommend that Sammy remain on risperidone for another 3 months of stability and then begin to taper this medication. You review the risks and benefits of long-term treatment with risperidone, pointing out that it may lead to abnormal movements upon withdrawal, and explain that you typically do not treat children with antipsychotics for more than one year continuously.

CASE CONTINUED: Comorbid symptoms

Since starting 7th grade, Sammy has worried excessively about making mistakes. He spends 6 hours each night on homework, which he often does not turn in because of anxiety about not getting answers perfectly right. Classmates notice that Sammy taps the door 3 times when he comes into the classroom and that he steps over the black tiles in the hallway.

Consider the presence and impact of comorbid OCD or ADHD, which can impair children’s quality of life more than tics themselves.¹⁵ Assessment scales can help you make a diagnosis and monitor treatment.

If you suspect OCD, the clinician-rated Children’s Yale Brown Obsessive Compulsive Scale is the gold standard for describing the phenomenology and measuring symptom severity. Additional scales to measure symptoms’ impact on family life include the Leyton Obsessional Inventory—child version, Family Accommodation Scale for OCD, and Child OCD Impact Scale.

ADHD scales include the Conners Parent Rating Scale—Revised, Conners Teacher Rating Scale—Revised, Swanson, Nolan, and Pelham, or the Vanderbilt ADHD Diagnostic Parent and Teacher Rating Scales. Because ADHD symptoms must be present in more than 1 environment to meet diagnostic criteria, ask parents and teachers to complete the Conners or Vanderbilt scales.

In children who present with a tic disorder plus a comorbid condition, prioritize treatment by determining which symptoms interfere with the child’s ability to function at school, at home, and in the social arena. Children who require treatment for >1 disorder often are referred initially for cognitive-behavioral therapy for OCD symptoms while receiving pharmacologic treatment for ADHD and/or Tourette syndrome. When necessary, it is usually safe to combine antipsychotics, stimulants, and selective serotonin reuptake inhibitors, although medication interactions should be reviewed in each specific case.

Related resources

• Woods DW. Managing Tourette syndrome: a behavioral intervention for children and adults. Therapist guide. New York, NY: Oxford University Press; 2008.
• Tourette Syndrome Association. www.tsa-usa.org.
• International OCD Foundation. www.ocfoundation.org.

Drug brand names

• Baclofen • Lioresal
• Botulinum toxin • Botox, Myobloc
• Clomipramine • Anafranil
• Clonidine • Catapres
• Guanfacine • Tenex
• Fluphenazine • Prolixin
• Flutamide • Eulexin
• Haloperidol • Haldol
• Mecamylamine • Inversine
• Nicotine patch • NicoDerm
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Tetrabenazine • Xenazine
• Ziprasidone • Geodon

Disclosures

Dr. Harris has received research support from the Translational Research Initiative at Cincinnati Children’s Hospital Medical Center.

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

Discuss this article

Sammy, age 7, is referred to you by his pediatrician because of a 4-week history of frequent eye blinking. His parents say he blinks a lot when bored but very little when playing baseball. They recall that he also has intermittently sniffed and nodded his head over the last 12 months. Neither Sammy nor his friends seem to be bothered by the blinking. Except for the tics, Sammy’s physical and mental status exams are normal.

Since preschool, Sammy’s teachers have complained that his backpack and desk are always a mess. Sammy is well-meaning but forgetful in his chores at home. A paternal uncle has head-turning movements, counts his steps, and becomes distressed if books on his shelf are not in alphabetical order.

Tics, such as strong eye blinks or repetitive shoulder shrugs, can distress a child or his/her parents, but the conditions associated with tic disorders often are more problematic than the tic disorder itself. High rates of comorbid conditions are recognized in persons with Tourette syndrome, including:

• obsessive-compulsive disorder (OCD) in >80%¹
• attention-deficit/hyperactivity disorder (ADHD) in ≤70%²
• anxiety disorders in 30%³
• rage, aggression, learning disabilities, and autism less commonly.

The strategy we recommend for managing tic disorders includes assessing tic severity, educating the family about the illness, determining whether a comorbid condition is present, and managing these conditions appropriately. Above all, we emphasize a risk-benefit analysis guided by the Hippocratic principle of “do no harm.”

Characteristics of tic disorders

You diagnose Sammy with Tourette syndrome because he meets DSM-IV-TR criteria of at least 2 motor tics and 1 vocal tic that have persisted for 1 year without more than a 3-month hiatus, with tic onset before age 18. Because tics may resemble other movement disorders, you rule out stereotypies, dystonia, chorea, ballism, and myoclonus (Table 1). You explain to his parents that Sammy’s condition is a heritable, neurobehavioral disorder that typically begins in childhood and is associated in families with OCD, ADHD, and autism spectrum disorders.

His parents ask about the difference between tics and other movements. You explain that eye-blinking tics—like other motor tics—appear as sudden, repetitive, stereotyped, nonrhythmic movements that involve discrete muscle groups. (View a video of a patient with tics.) Simple motor tics are focal movements involving 1 group of muscles, whereas complex tics are sequential patterns of movement that involve >1 muscle group or resemble purposeful movements (Table 2).

Table 1

Features of 5 movement disorders that may resemble tics

Table 2

Characteristics of simple and complex motor and vocal tics*

Older children frequently describe a premonitory urge prior to the tic. Patients typically can suppress tics for a transient period of time, although during tic suppression they usually feel restless and anticipate performing their tic. The ultimate performance of the tic brings relief. Tic suppression also occurs during focused activity. Emotional stress, fatigue, illness, or boredom can exacerbate tics.

To begin monitoring Sammy’s clinical course, you administer 3 assessment tools described inTable 3. You explain to Sammy’s parents that these tests will be repeated yearly or when tics worsen. However, you tell his parents that these scores alone will not determine present or future clinical decisions, including treatments. You also recommend that they connect with support groups on the Tourette Syndrome Association (TSA) Web site.

CASE CONTINUED: Changes over time

Sammy’s parents appreciate your explanation and say they will share information from the TSA Web site with Sammy’s principal, teachers, and classmates. The family agrees to return in 6 months or sooner if the tics worsen.

By age 8, Sammy develops multiple tics: facial grimacing, looking upwards, punching movements, whistling, and throat clearing. He is slightly bothered by these tics, and his friends have asked him about them. He tells them he has Tourette syndrome, and that usually ends the questioning. He returns for a follow-up visit because his parents notice a dramatic increase in his tics after Sammy’s father loses his job.

Treatment options

When deciding to treat a child’s tics, the first step is to determine whether to pursue a nonpharmacologic or pharmacologic approach (Algorithm). To tailor an approach most suited for an individual child, discuss with the family their feelings about therapy and medications. This information—along with tic severity—will help determine a treatment plan.

Behavior therapy and medication are management strategies; neither can cure a tic disorder. The most conservative approach to tic treatment is to:

• provide the child and family with basic guidelines for managing tics
• help alleviate environmental stress and other potential triggers.

Algorithm: Recommended treatment of tics in children and adolescents

CASE CONTINUED: A first intervention

You discuss treatment options with Sammy’s family, and they view medication as a last resort. Sammy does not seem to be bothered by his tics, and his parents do not wish to start him on daily medications. Given this situation, habit reversal therapy (HRT) is appropriate for Sammy because he is old enough to participate in HRT to reduce his tics.

HRT is an effective nonpharmacologic approach to help children with tics.⁴ Its 3 components are:

• awareness training
• competing response training
• social support.⁵

This simplified version of the original HRT can be completed in eight 1-hour sessions. Good candidates are patients who are cognitively mature enough to understand the therapy’s goals and compliant with frequent clinic visits. They also must practice the strategies at home.

It should not be difficult for psychiatrists to learn HRT—or refer to therapists who are willing to learn it—with the available instructional manual.

CASE CONTINUED: Practicing alternatives

You ask Sammy to imitate his tics. After helping him become more aware of his tics, you encourage him to develop a more socially appropriate movement to engage in whenever he feels the urge to punch. Sammy chooses to clench his fist in his pocket. He also learns to breathe in whenever he has an urge to whistle. you advise Sammy’s parents to reward his efforts to suppress the tics. He practices the strategies daily.

At age 12, Sammy returns to your office. He has begun to have frequent neck-jerking tics, which cause neck pain and daily headaches. He also is slapping his thigh and having frequent vocal tics characterized by loud shrieking. The vocal tics are disruptive in class, even though Sammy sits toward the back of the room. Sammy’s classmates tease him, and he is very frustrated.

Medication approach

The decision to start a medication for tics is complex. Scores from the YGTSS, PUTS, and GTS-QOL scales (Table 3) provide only a partial clinical picture. This decision should be reached after a detailed discussion with the family about benefits and risks of medications and ensuring that everyone’s expectations are reasonable.

A variety of medications are available to treat patients with tics (Table 4). No medication can completely eliminate tics, however, and many have substantial side effects. Before initiating medical treatment, consider 3 questions:

• Is moderate or severe pain involved?
• Is there significant functional interference?
• Is there significant social disruption despite efforts to optimize the social environment for the child?

Sammy’s frequent neck-jerking tics now cause chronic daily headaches, and his shrieking vocal tics are interfering with classroom activities, so we recommended a 3-month trial of guanfacine following the dosing schedule in Table 4.

Table 3

3 scales for assessing tic severity and impact on functioning

Table 4

Medications with evidence of tic-suppressing effects*

The first-line pharmacologic agent for tic suppression generally is an alpha-adrenergic medication, unless the tics are severe.⁶

Clonidine and guanfacine usually are started at low doses and increased gradually. Although not as effective as neuroleptics, alpha-adrenergics have a lower potential for side effects and are easier to use because no laboratory tests need to be monitored. Adverse effects associated with alpha-adrenergic medications include sedation, dry mouth, dizziness, headache, and rebound hypertension if discontinued abruptly.

If tics are causing pain, some clinicians prefer conservative measures such as heat or ice, massage, analgesics, relaxation therapy, and reassurance.

Second-line agents include typical and atypical antipsychotics. Haloperidol and pimozide have shown efficacy in reducing tics in placebo- controlled studies,^7,8 as have risperidone (in 4 randomized controlled trials [RCTs]) and ziprasidone (in 1 RCT).^9,10 The emergence of serious side effects is a risk for both typical and atypical antipsychotics (Table 5).

Table 5

Potential adverse effects of antipsychotic treatment in children*

As part of your informed consent discussion, weigh the risk of side effects against the benefits of treatment. Point out to patients and their families that they can expect to see a decrease in tic frequency, but symptoms will not necessarily disappear with any medication. We tell our patients that with antipsychotics the best we can hope for is to reduce tic frequency by approximately one-half.⁶

When treating tics, start with 1 medication. However, if the tics are severe enough to require more than 1 medication, check for drug interactions.

Third-line agents. Agents that have not been tested in placebo-controlled trials can be considered third line; these are listed as category C (supported by open-label studies) in Table 4. Botulinum toxin injection has been found to be effective for motor and vocal tics.^11,12 Botulinum toxin and implantation of deep brain stimulators¹³ are invasive options and generally are reserved for severe, treatment-resistant tics.

CASE CONTINUED: Managing antipsychotics

After trying guanfacine for 12 weeks, Sammy notices no tic reduction. His parents consent to a low dose of risperidone. you review with them the American Psychiatric Association (APA)/American Diabetes Association (ADA) guidelines¹⁴ for managing metabolic problems in patients treated with atypical antipsychotics.

As instructed in the APA/ADA guidelines, obtain baseline measurements and monitor for metabolic effects of antipsychotic therapy over time (Table 6). Sammy starts risperidone at 0.5 mg once daily. After 2 weeks, he notices a decrease in his tics. At the 3-month visit after starting risperidone, he is happy with his risperidone dose and does not want to increase it. He has gained 3 pounds, and you instruct him to eat a well-balanced diet and exercise routinely. At the 6-month visit, his tics are minimal and his weight has stabilized.

Table 6

Children receiving antipsychotics: monitoring recommendations

You recommend that Sammy remain on risperidone for another 3 months of stability and then begin to taper this medication. You review the risks and benefits of long-term treatment with risperidone, pointing out that it may lead to abnormal movements upon withdrawal, and explain that you typically do not treat children with antipsychotics for more than one year continuously.

CASE CONTINUED: Comorbid symptoms

Since starting 7th grade, Sammy has worried excessively about making mistakes. He spends 6 hours each night on homework, which he often does not turn in because of anxiety about not getting answers perfectly right. Classmates notice that Sammy taps the door 3 times when he comes into the classroom and that he steps over the black tiles in the hallway.

Consider the presence and impact of comorbid OCD or ADHD, which can impair children’s quality of life more than tics themselves.¹⁵ Assessment scales can help you make a diagnosis and monitor treatment.

If you suspect OCD, the clinician-rated Children’s Yale Brown Obsessive Compulsive Scale is the gold standard for describing the phenomenology and measuring symptom severity. Additional scales to measure symptoms’ impact on family life include the Leyton Obsessional Inventory—child version, Family Accommodation Scale for OCD, and Child OCD Impact Scale.

ADHD scales include the Conners Parent Rating Scale—Revised, Conners Teacher Rating Scale—Revised, Swanson, Nolan, and Pelham, or the Vanderbilt ADHD Diagnostic Parent and Teacher Rating Scales. Because ADHD symptoms must be present in more than 1 environment to meet diagnostic criteria, ask parents and teachers to complete the Conners or Vanderbilt scales.

In children who present with a tic disorder plus a comorbid condition, prioritize treatment by determining which symptoms interfere with the child’s ability to function at school, at home, and in the social arena. Children who require treatment for >1 disorder often are referred initially for cognitive-behavioral therapy for OCD symptoms while receiving pharmacologic treatment for ADHD and/or Tourette syndrome. When necessary, it is usually safe to combine antipsychotics, stimulants, and selective serotonin reuptake inhibitors, although medication interactions should be reviewed in each specific case.

Related resources

• Woods DW. Managing Tourette syndrome: a behavioral intervention for children and adults. Therapist guide. New York, NY: Oxford University Press; 2008.
• Tourette Syndrome Association. www.tsa-usa.org.
• International OCD Foundation. www.ocfoundation.org.

Drug brand names

• Baclofen • Lioresal
• Botulinum toxin • Botox, Myobloc
• Clomipramine • Anafranil
• Clonidine • Catapres
• Guanfacine • Tenex
• Fluphenazine • Prolixin
• Flutamide • Eulexin
• Haloperidol • Haldol
• Mecamylamine • Inversine
• Nicotine patch • NicoDerm
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Tetrabenazine • Xenazine
• Ziprasidone • Geodon

Disclosures

Dr. Harris has received research support from the Translational Research Initiative at Cincinnati Children’s Hospital Medical Center.

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

Discuss this article

Sammy, age 7, is referred to you by his pediatrician because of a 4-week history of frequent eye blinking. His parents say he blinks a lot when bored but very little when playing baseball. They recall that he also has intermittently sniffed and nodded his head over the last 12 months. Neither Sammy nor his friends seem to be bothered by the blinking. Except for the tics, Sammy’s physical and mental status exams are normal.

Since preschool, Sammy’s teachers have complained that his backpack and desk are always a mess. Sammy is well-meaning but forgetful in his chores at home. A paternal uncle has head-turning movements, counts his steps, and becomes distressed if books on his shelf are not in alphabetical order.

Tics, such as strong eye blinks or repetitive shoulder shrugs, can distress a child or his/her parents, but the conditions associated with tic disorders often are more problematic than the tic disorder itself. High rates of comorbid conditions are recognized in persons with Tourette syndrome, including:

• obsessive-compulsive disorder (OCD) in >80%¹
• attention-deficit/hyperactivity disorder (ADHD) in ≤70%²
• anxiety disorders in 30%³
• rage, aggression, learning disabilities, and autism less commonly.

The strategy we recommend for managing tic disorders includes assessing tic severity, educating the family about the illness, determining whether a comorbid condition is present, and managing these conditions appropriately. Above all, we emphasize a risk-benefit analysis guided by the Hippocratic principle of “do no harm.”

Characteristics of tic disorders

You diagnose Sammy with Tourette syndrome because he meets DSM-IV-TR criteria of at least 2 motor tics and 1 vocal tic that have persisted for 1 year without more than a 3-month hiatus, with tic onset before age 18. Because tics may resemble other movement disorders, you rule out stereotypies, dystonia, chorea, ballism, and myoclonus (Table 1). You explain to his parents that Sammy’s condition is a heritable, neurobehavioral disorder that typically begins in childhood and is associated in families with OCD, ADHD, and autism spectrum disorders.

His parents ask about the difference between tics and other movements. You explain that eye-blinking tics—like other motor tics—appear as sudden, repetitive, stereotyped, nonrhythmic movements that involve discrete muscle groups. (View a video of a patient with tics.) Simple motor tics are focal movements involving 1 group of muscles, whereas complex tics are sequential patterns of movement that involve >1 muscle group or resemble purposeful movements (Table 2).

Table 1

Features of 5 movement disorders that may resemble tics

Table 2

Characteristics of simple and complex motor and vocal tics*

Older children frequently describe a premonitory urge prior to the tic. Patients typically can suppress tics for a transient period of time, although during tic suppression they usually feel restless and anticipate performing their tic. The ultimate performance of the tic brings relief. Tic suppression also occurs during focused activity. Emotional stress, fatigue, illness, or boredom can exacerbate tics.

To begin monitoring Sammy’s clinical course, you administer 3 assessment tools described inTable 3. You explain to Sammy’s parents that these tests will be repeated yearly or when tics worsen. However, you tell his parents that these scores alone will not determine present or future clinical decisions, including treatments. You also recommend that they connect with support groups on the Tourette Syndrome Association (TSA) Web site.

CASE CONTINUED: Changes over time

Sammy’s parents appreciate your explanation and say they will share information from the TSA Web site with Sammy’s principal, teachers, and classmates. The family agrees to return in 6 months or sooner if the tics worsen.

By age 8, Sammy develops multiple tics: facial grimacing, looking upwards, punching movements, whistling, and throat clearing. He is slightly bothered by these tics, and his friends have asked him about them. He tells them he has Tourette syndrome, and that usually ends the questioning. He returns for a follow-up visit because his parents notice a dramatic increase in his tics after Sammy’s father loses his job.

Treatment options

When deciding to treat a child’s tics, the first step is to determine whether to pursue a nonpharmacologic or pharmacologic approach (Algorithm). To tailor an approach most suited for an individual child, discuss with the family their feelings about therapy and medications. This information—along with tic severity—will help determine a treatment plan.

Behavior therapy and medication are management strategies; neither can cure a tic disorder. The most conservative approach to tic treatment is to:

• provide the child and family with basic guidelines for managing tics
• help alleviate environmental stress and other potential triggers.

Algorithm: Recommended treatment of tics in children and adolescents

CASE CONTINUED: A first intervention

You discuss treatment options with Sammy’s family, and they view medication as a last resort. Sammy does not seem to be bothered by his tics, and his parents do not wish to start him on daily medications. Given this situation, habit reversal therapy (HRT) is appropriate for Sammy because he is old enough to participate in HRT to reduce his tics.

HRT is an effective nonpharmacologic approach to help children with tics.⁴ Its 3 components are:

• awareness training
• competing response training
• social support.⁵

This simplified version of the original HRT can be completed in eight 1-hour sessions. Good candidates are patients who are cognitively mature enough to understand the therapy’s goals and compliant with frequent clinic visits. They also must practice the strategies at home.

It should not be difficult for psychiatrists to learn HRT—or refer to therapists who are willing to learn it—with the available instructional manual.

CASE CONTINUED: Practicing alternatives

You ask Sammy to imitate his tics. After helping him become more aware of his tics, you encourage him to develop a more socially appropriate movement to engage in whenever he feels the urge to punch. Sammy chooses to clench his fist in his pocket. He also learns to breathe in whenever he has an urge to whistle. you advise Sammy’s parents to reward his efforts to suppress the tics. He practices the strategies daily.

At age 12, Sammy returns to your office. He has begun to have frequent neck-jerking tics, which cause neck pain and daily headaches. He also is slapping his thigh and having frequent vocal tics characterized by loud shrieking. The vocal tics are disruptive in class, even though Sammy sits toward the back of the room. Sammy’s classmates tease him, and he is very frustrated.

Medication approach

The decision to start a medication for tics is complex. Scores from the YGTSS, PUTS, and GTS-QOL scales (Table 3) provide only a partial clinical picture. This decision should be reached after a detailed discussion with the family about benefits and risks of medications and ensuring that everyone’s expectations are reasonable.

A variety of medications are available to treat patients with tics (Table 4). No medication can completely eliminate tics, however, and many have substantial side effects. Before initiating medical treatment, consider 3 questions:

• Is moderate or severe pain involved?
• Is there significant functional interference?
• Is there significant social disruption despite efforts to optimize the social environment for the child?

Sammy’s frequent neck-jerking tics now cause chronic daily headaches, and his shrieking vocal tics are interfering with classroom activities, so we recommended a 3-month trial of guanfacine following the dosing schedule in Table 4.

Table 3

3 scales for assessing tic severity and impact on functioning

Table 4

Medications with evidence of tic-suppressing effects*

The first-line pharmacologic agent for tic suppression generally is an alpha-adrenergic medication, unless the tics are severe.⁶

Clonidine and guanfacine usually are started at low doses and increased gradually. Although not as effective as neuroleptics, alpha-adrenergics have a lower potential for side effects and are easier to use because no laboratory tests need to be monitored. Adverse effects associated with alpha-adrenergic medications include sedation, dry mouth, dizziness, headache, and rebound hypertension if discontinued abruptly.

If tics are causing pain, some clinicians prefer conservative measures such as heat or ice, massage, analgesics, relaxation therapy, and reassurance.

Second-line agents include typical and atypical antipsychotics. Haloperidol and pimozide have shown efficacy in reducing tics in placebo- controlled studies,^7,8 as have risperidone (in 4 randomized controlled trials [RCTs]) and ziprasidone (in 1 RCT).^9,10 The emergence of serious side effects is a risk for both typical and atypical antipsychotics (Table 5).

Table 5

Potential adverse effects of antipsychotic treatment in children*

As part of your informed consent discussion, weigh the risk of side effects against the benefits of treatment. Point out to patients and their families that they can expect to see a decrease in tic frequency, but symptoms will not necessarily disappear with any medication. We tell our patients that with antipsychotics the best we can hope for is to reduce tic frequency by approximately one-half.⁶

When treating tics, start with 1 medication. However, if the tics are severe enough to require more than 1 medication, check for drug interactions.

Third-line agents. Agents that have not been tested in placebo-controlled trials can be considered third line; these are listed as category C (supported by open-label studies) in Table 4. Botulinum toxin injection has been found to be effective for motor and vocal tics.^11,12 Botulinum toxin and implantation of deep brain stimulators¹³ are invasive options and generally are reserved for severe, treatment-resistant tics.

CASE CONTINUED: Managing antipsychotics

After trying guanfacine for 12 weeks, Sammy notices no tic reduction. His parents consent to a low dose of risperidone. you review with them the American Psychiatric Association (APA)/American Diabetes Association (ADA) guidelines¹⁴ for managing metabolic problems in patients treated with atypical antipsychotics.

As instructed in the APA/ADA guidelines, obtain baseline measurements and monitor for metabolic effects of antipsychotic therapy over time (Table 6). Sammy starts risperidone at 0.5 mg once daily. After 2 weeks, he notices a decrease in his tics. At the 3-month visit after starting risperidone, he is happy with his risperidone dose and does not want to increase it. He has gained 3 pounds, and you instruct him to eat a well-balanced diet and exercise routinely. At the 6-month visit, his tics are minimal and his weight has stabilized.

Table 6

Children receiving antipsychotics: monitoring recommendations

You recommend that Sammy remain on risperidone for another 3 months of stability and then begin to taper this medication. You review the risks and benefits of long-term treatment with risperidone, pointing out that it may lead to abnormal movements upon withdrawal, and explain that you typically do not treat children with antipsychotics for more than one year continuously.

CASE CONTINUED: Comorbid symptoms

Since starting 7th grade, Sammy has worried excessively about making mistakes. He spends 6 hours each night on homework, which he often does not turn in because of anxiety about not getting answers perfectly right. Classmates notice that Sammy taps the door 3 times when he comes into the classroom and that he steps over the black tiles in the hallway.

Consider the presence and impact of comorbid OCD or ADHD, which can impair children’s quality of life more than tics themselves.¹⁵ Assessment scales can help you make a diagnosis and monitor treatment.

If you suspect OCD, the clinician-rated Children’s Yale Brown Obsessive Compulsive Scale is the gold standard for describing the phenomenology and measuring symptom severity. Additional scales to measure symptoms’ impact on family life include the Leyton Obsessional Inventory—child version, Family Accommodation Scale for OCD, and Child OCD Impact Scale.

ADHD scales include the Conners Parent Rating Scale—Revised, Conners Teacher Rating Scale—Revised, Swanson, Nolan, and Pelham, or the Vanderbilt ADHD Diagnostic Parent and Teacher Rating Scales. Because ADHD symptoms must be present in more than 1 environment to meet diagnostic criteria, ask parents and teachers to complete the Conners or Vanderbilt scales.

In children who present with a tic disorder plus a comorbid condition, prioritize treatment by determining which symptoms interfere with the child’s ability to function at school, at home, and in the social arena. Children who require treatment for >1 disorder often are referred initially for cognitive-behavioral therapy for OCD symptoms while receiving pharmacologic treatment for ADHD and/or Tourette syndrome. When necessary, it is usually safe to combine antipsychotics, stimulants, and selective serotonin reuptake inhibitors, although medication interactions should be reviewed in each specific case.

Related resources

• Woods DW. Managing Tourette syndrome: a behavioral intervention for children and adults. Therapist guide. New York, NY: Oxford University Press; 2008.
• Tourette Syndrome Association. www.tsa-usa.org.
• International OCD Foundation. www.ocfoundation.org.

Drug brand names

• Baclofen • Lioresal
• Botulinum toxin • Botox, Myobloc
• Clomipramine • Anafranil
• Clonidine • Catapres
• Guanfacine • Tenex
• Fluphenazine • Prolixin
• Flutamide • Eulexin
• Haloperidol • Haldol
• Mecamylamine • Inversine
• Nicotine patch • NicoDerm
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Tetrabenazine • Xenazine
• Ziprasidone • Geodon

Disclosures

Dr. Harris has received research support from the Translational Research Initiative at Cincinnati Children’s Hospital Medical Center.

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

Discuss this article

Most psychiatrists have encountered patients who report distressing symptoms when they have forgotten to take their antidepressant for a few days or during changes in the medication regimen. A discontinuation syndrome can occur with almost any antidepressant, highlighting the need to slowly taper these medications when discontinuation is part of a treatment plan.

This article discusses antidepressant discontinuation syndrome (ADS) in a patient who experienced substantial distress after a rapid antidepressant taper in preparation for electroconvulsive therapy (ECT). My goal is to raise awareness of ADS, promote early detection of the syndrome, and address proper prevention and management strategies.

CASE REPORT: Feeling ‘worse than ever’

Mr. J, a 32-year-old tax accountant, is hospitalized for a major depressive episode (MDE) associated with deteriorating function and suicidal ideation. This second lifetime MDE started 8 months before his admission to an inpatient mood disorders unit.

Mr. J initially was treated with fluoxetine, up to 40 mg/d across 14 weeks, with good tolerability but no significant benefit. His psychiatrist switched Mr. J to bupropion but stopped it after 4 weeks because of side effects—including headaches, insomnia, and tremor—and limited antidepressant benefit. Venlafaxine XR was initiated next, at 150 mg/d within the first 2 weeks, increased to 225 mg/d at week 6, then titrated to 300 mg/d at week 10. After 10 weeks, aripiprazole, 5 mg/d, was added because Mr. J showed only partial, limited response to venlafaxine XR and this antipsychotic is indicated for adjunctive treatment of major depressive disorder.

Mr. J reported mild, transient restlessness but otherwise he tolerated the medications well, and he claimed excellent adherence. After 6 additional weeks of treatment, however, Mr. J was hospitalized because of persistent severely depressed mood, increasing suicidal ideation, and inability to function at work.

On admission, Mr. J is evaluated and agrees to ECT. To meet the ECT service’s protocol, venlafaxine XR is reduced to 150 mg/d for 2 days and then stopped when ECT is started. Aripiprazole is continued at 5 mg/d.

Mr. J tolerates the first ECT treatment well, but the morning before his second treatment he complains of feeling “worse than ever.” An agitated Mr. J reports dramatically intensified suicidal ideation—much more intrusive than before he was hospitalized. He also complains of diffuse muscle aches and cramps, runny nose, nausea, headache, and burning sensations in both arms and hands. He withdraws consent for ECT and returns to the mood disorders unit for ongoing treatment.

Could this be ADS?

Yes, it could. In this case, the inpatient psychiatrist and treatment team were lulled into a false sense of security by Mr. J’s history of few side effects with various treatments and medication changes. The ECT service wanted the patient off venlafaxine XR before beginning ECT, and the treatment team believed a quick taper would not cause discontinuation symptoms because Mr. J was taking an “extended-release” medication.

Within 72 hours, Mr. J went from taking 300 mg/d of venlafaxine XR to none. Within 2 days of cessation, he complained of symptoms that could characterize a discontinuation syndrome. A potential red herring in this case is that the patient complained of feeling worse after his first ECT treatment, and one might erroneously think the myalgias, headache, and other somatic symptoms were side effects of ECT and/or anesthesia.

Typical ADS symptoms

Nearly all antidepressant classes are associated with ADS. Symptoms vary from patient to patient but typically include the “FINISH” syndrome: flu-like symptoms, ###bold/bold###nsomnia, nausea, ###bold/bold###mbalance, sensory disturbances, and hyperarousal (anxiety/agitation) (Table 1).¹

Adverse effects after stopping tricyclic antidepressants have been well documented. They may include FINISH syndrome features as well as cholinergic overdrive or “rebound” such as abdominal cramping and diarrhea.^2-4 Reports of ADS after patients stopped selective serotonin reuptake inhibitors (SSRIs) emerged soon after these agents were introduced.^5-7 Similarly, ADS has been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine,^8-10 venlafaxine XR,¹¹ and duloxetine.¹² ADS symptoms are similar with SSRIs and SNRIs, generally without the anticholinergic effects associated with tricyclic antidepressant discontinuation.

Fewer reports of discontinuation syndrome exist for bupropion, mirtazapine, monoamine oxidase inhibitors (MAOIs), and nefazodone.^13-17 Discontinuation-emergent syndromes with these non-SSRI/non-SNRI antidepressants tend to present differently. With MAOIs, for example, neuropsychiatric symptoms such as severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, delirium, and paranoid psychosis can be prominent.¹⁷

The prevalence of ADS is unclear, and published estimates vary widely because of the lack of large controlled studies. ADS rates with SSRIs/SNRIs have been reported from as low as 0% for fluoxetine to higher rates for shorter half-life antidepressants:

• 2.2% with sertraline
• 14% with fluvoxamine
• 20% with paroxetine
• 30.8% with clomipramine.

These rates come from a retrospective case note review of patients who discontinued antidepressants under supervision.¹⁸ In a small cohort of outpatients being treated for major depressive disorder, stopping venlafaxine XR was associated with discontinuation symptoms for the next 3 days in 7 of 9 patients (78%), compared with 2 of 9 patients (22%) stopping placebo.¹¹

Diagnostic criteria have been proposed for ADS associated with serotonin (5-HT) reuptake inhibitors.^19-22 Proposed ADS definitions differ somewhat, but essentially 3 features guide the diagnosis:

• appearance of characteristic symptoms (Table 2)^21,23
• timing of those symptoms, which usually emerge within 1 week of abrupt cessation or marked reduction of the antidepressant
• symptoms generally are mild, short-lived, self-limiting, and/or rapidly reversed by restarting the original antidepressant.

Evidence suggests shorter half-life antidepressants may be associated with the highest risk for ADS, but other risk factors remain presumptive (Table 3).

Table 1

FINISH: Symptoms of antidepressant discontinuation syndrome

Table 2

ADS symptoms can range across a variety of system clusters

Table 3

Possible patient risk factors for developing ADS*

What causes ADS?

Although the exact cause of ADS is unknown, the literature proposes several theories.

Because of the central serotonin system’s complex connections, acute reduction in synaptic serotonin when an SSRI or SNRI is abruptly or too quickly stopped may be the first in a cascade of steps affecting transmission of multiple monoamines. Parallels have been drawn between the phenomenon observed with rapid depletion of tryptophan—the essential amino acid precursor for the synthesis of 5-HT—and ADS seen with abrupt discontinuation of serotonergic antidepressants. This suggests that acute drops in neurotransmitter levels can precipitate neuropsychiatric and somatic manifestations of ADS.²⁴

Patients’ uncomfortable symptoms likely are caused by the serotonin, norepinephrine, and cholinergic systems and their complex interactions.²⁵ Individual genetic factors may influence patients’ vulnerability for ADS.

Managing ADS

Awareness and prevention. ADS can be misinterpreted as side effects of newly started treatment after an antidepressant is stopped. In Mr. J’s case, the appearance of muscle aches, headaches, and other ADS symptoms after ECT was started easily could have been perceived as adverse effects of ECT. Mr. J’s agitation and increased suicidal ideation could lead a clinician to mistakenly think that MDE was worsening because the antidepressant was stopped before ECT became effective. Being aware of ADS can prevent misdiagnosis and allow you to quickly identify the condition, manage the reversible syndrome, and continue with new treatment plan—in this case, ECT.

You can help prevent ADS by educating patients about the need to adhere to antidepressant regimens and to avoid missing doses. Consider ADS risk factors—particularly medications’ half-lives—before you start, change, or stop antidepressant therapy. Gradually taper all antidepressants being discontinued, with the possible exception of fluoxetine (which, including its active metabolite, has an elimination half-life of approximately 1 to 2 weeks).

Tapering antidepressants is more art than science because we have no controlled data to support any particular tapering regimen. Tailor the taper duration based on each patient’s response to sequential dosage reductions. Antidepressants with shorter half-lives—such as venlafaxine or paroxetine—may need to be tapered more slowly, perhaps by reducing the dosage by 25% every 4 to 6 weeks. If you plan to switch medications, this process may be expedited during a cross-taper to another antidepressant. You still may see discontinuation symptoms, however, depending on which new agent is chosen and which is being stopped.

Treating ADS. Appropriately recognizing ADS risk and slowly tapering antidepressants as needed usually prevents clinically significant distress associated with discontinuation. For some patients, however, ADS may be particularly severe or prolonged, or may emerge at the end of a slow taper.

Challenging cases may be more likely with paroxetine or venlafaxine—even the extended-release or controlled-release preparations. The elimination half-life of paroxetine is 15 to 20 hours, and the half-lives of venlafaxine and venlafaxine XR are 5 to 11 hours. Desvenlafaxine’s half-life is 11 hours, and product labeling of this enantiomer of racemic venlafaxine notes that discontinuation symptoms have occurred.²⁶ ADS treatment depends on the severity of the reaction and whether or not further antidepressant therapy is necessary.

For mild ADS, reassurance and treatment focused on specific symptoms—such as sedative-hypnotics for insomnia or benzodiazepines for anxiety—may be all that is needed, because ADS tends to gradually resolve over an average of 10 days.²⁷

For more severe ADS, or when ongoing antidepressant therapy is indicated, restarting the recently withdrawn antidepressant at the pre-ADS dosage typically resolves the syndrome within 24 hours. Then employ a slower, more cautious taper when next attempting to discontinue that antidepressant.

Another option. An alternate management strategy is to substitute fluoxetine to suppress ADS associated with shorter half-life SSRIs or SNRIs. Case reports^18,20,28 suggest that fluoxetine, 5 to 20 mg/d, can be used to ameliorate venlafaxine-induced ADS. Fluoxetine can be tried as monotherapy for 1 to 2 weeks and then rapidly tapered or stopped. Others have suggested combination therapy, such as:

• restarting venlafaxine at the pre-ADS dose plus fluoxetine, 20 mg/d
• tapering venlafaxine by 50% every 5 days until stopped
• reducing fluoxetine 1 week later to 10 mg/d for 5 days
• then stopping fluoxetine.²⁸

In general, SSRIs should not be co-administered with SNRIs long-term because of potential additive adverse effects such as serotonin syndrome. Combining fluoxetine with an SNRI such as venlafaxine for the purpose of tapering off venlafaxine and reducing ADS risk probably is safe, however, as long as the fluoxetine dose is low (5 to 20 mg) and SNRI reduction begins immediately, with a plan for complete tapering.

CASE CONTINUED: ECT treatment proceeds

Venlafaxine XR is not restarted to address Mr. J’s suspected ADS because of concerns about potential increased risk for cardiac events (asystole, prolonged bradycardia) during ECT with concomitant venlafaxine use.^29,30 Fluoxetine, which rarely may prolong ECT-induced seizures, is deemed a safer choice and is started immediately at 20 mg/d.

Because of Mr. J’s other symptoms, we prescribe lorazepam, 0.5 mg bid, for anxiety for 2 days; increase aripiprazole to 5 mg bid for agitation; and add zolpidem, 10 mg at bedtime, for insomnia. The following day, Mr. J reports substantial relief from ADS symptoms, including myalgias, paresthesias, and suicidal ideation.^21,23

His second ECT treatment is administered the next day, followed by a successful course of 9 treatments and partial remission of the MDE within 3 weeks. Fluoxetine is reduced to 10 mg/d one week into the ECT series, then discontinued one week later. No signs of emergent ADS are seen at discharge or 2-week outpatient follow-up. Mr. J achieves full remission with maintenance ECT plus bedtime doses of mirtazapine, 30 mg, and aripiprazole, 7.5 mg, across 6 months of follow-up care.

Related resources

• Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(suppl 4):27-30.
• American Family Physician. Patient handout on antidepressant discontinuation. www.aafp.org/afp/2006/0801/p457.html.
• Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77-87. See appendix for discontinuation-emergent signs and symptoms checklist.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Clomipramine • Anafranil
• Desvenlafaxine • Pristiq
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor
• Venlafaxine extended-release • Effexor XR
• Zolpidem • Ambien

Disclosure

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

Acknowledgment

When Dr. Muzina submitted this article to Current Psychiatry, he was director, Center for Mood Disorders Treatment and Research, Cleveland Clinic Neurological Institute, Cleveland, OH.

Discuss this article

Most psychiatrists have encountered patients who report distressing symptoms when they have forgotten to take their antidepressant for a few days or during changes in the medication regimen. A discontinuation syndrome can occur with almost any antidepressant, highlighting the need to slowly taper these medications when discontinuation is part of a treatment plan.

This article discusses antidepressant discontinuation syndrome (ADS) in a patient who experienced substantial distress after a rapid antidepressant taper in preparation for electroconvulsive therapy (ECT). My goal is to raise awareness of ADS, promote early detection of the syndrome, and address proper prevention and management strategies.

CASE REPORT: Feeling ‘worse than ever’

Mr. J, a 32-year-old tax accountant, is hospitalized for a major depressive episode (MDE) associated with deteriorating function and suicidal ideation. This second lifetime MDE started 8 months before his admission to an inpatient mood disorders unit.

Mr. J initially was treated with fluoxetine, up to 40 mg/d across 14 weeks, with good tolerability but no significant benefit. His psychiatrist switched Mr. J to bupropion but stopped it after 4 weeks because of side effects—including headaches, insomnia, and tremor—and limited antidepressant benefit. Venlafaxine XR was initiated next, at 150 mg/d within the first 2 weeks, increased to 225 mg/d at week 6, then titrated to 300 mg/d at week 10. After 10 weeks, aripiprazole, 5 mg/d, was added because Mr. J showed only partial, limited response to venlafaxine XR and this antipsychotic is indicated for adjunctive treatment of major depressive disorder.

Mr. J reported mild, transient restlessness but otherwise he tolerated the medications well, and he claimed excellent adherence. After 6 additional weeks of treatment, however, Mr. J was hospitalized because of persistent severely depressed mood, increasing suicidal ideation, and inability to function at work.

On admission, Mr. J is evaluated and agrees to ECT. To meet the ECT service’s protocol, venlafaxine XR is reduced to 150 mg/d for 2 days and then stopped when ECT is started. Aripiprazole is continued at 5 mg/d.

Mr. J tolerates the first ECT treatment well, but the morning before his second treatment he complains of feeling “worse than ever.” An agitated Mr. J reports dramatically intensified suicidal ideation—much more intrusive than before he was hospitalized. He also complains of diffuse muscle aches and cramps, runny nose, nausea, headache, and burning sensations in both arms and hands. He withdraws consent for ECT and returns to the mood disorders unit for ongoing treatment.

Could this be ADS?

Yes, it could. In this case, the inpatient psychiatrist and treatment team were lulled into a false sense of security by Mr. J’s history of few side effects with various treatments and medication changes. The ECT service wanted the patient off venlafaxine XR before beginning ECT, and the treatment team believed a quick taper would not cause discontinuation symptoms because Mr. J was taking an “extended-release” medication.

Within 72 hours, Mr. J went from taking 300 mg/d of venlafaxine XR to none. Within 2 days of cessation, he complained of symptoms that could characterize a discontinuation syndrome. A potential red herring in this case is that the patient complained of feeling worse after his first ECT treatment, and one might erroneously think the myalgias, headache, and other somatic symptoms were side effects of ECT and/or anesthesia.

Typical ADS symptoms

Nearly all antidepressant classes are associated with ADS. Symptoms vary from patient to patient but typically include the “FINISH” syndrome: flu-like symptoms, ###bold/bold###nsomnia, nausea, ###bold/bold###mbalance, sensory disturbances, and hyperarousal (anxiety/agitation) (Table 1).¹

Adverse effects after stopping tricyclic antidepressants have been well documented. They may include FINISH syndrome features as well as cholinergic overdrive or “rebound” such as abdominal cramping and diarrhea.^2-4 Reports of ADS after patients stopped selective serotonin reuptake inhibitors (SSRIs) emerged soon after these agents were introduced.^5-7 Similarly, ADS has been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine,^8-10 venlafaxine XR,¹¹ and duloxetine.¹² ADS symptoms are similar with SSRIs and SNRIs, generally without the anticholinergic effects associated with tricyclic antidepressant discontinuation.

Fewer reports of discontinuation syndrome exist for bupropion, mirtazapine, monoamine oxidase inhibitors (MAOIs), and nefazodone.^13-17 Discontinuation-emergent syndromes with these non-SSRI/non-SNRI antidepressants tend to present differently. With MAOIs, for example, neuropsychiatric symptoms such as severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, delirium, and paranoid psychosis can be prominent.¹⁷

The prevalence of ADS is unclear, and published estimates vary widely because of the lack of large controlled studies. ADS rates with SSRIs/SNRIs have been reported from as low as 0% for fluoxetine to higher rates for shorter half-life antidepressants:

• 2.2% with sertraline
• 14% with fluvoxamine
• 20% with paroxetine
• 30.8% with clomipramine.

These rates come from a retrospective case note review of patients who discontinued antidepressants under supervision.¹⁸ In a small cohort of outpatients being treated for major depressive disorder, stopping venlafaxine XR was associated with discontinuation symptoms for the next 3 days in 7 of 9 patients (78%), compared with 2 of 9 patients (22%) stopping placebo.¹¹

Diagnostic criteria have been proposed for ADS associated with serotonin (5-HT) reuptake inhibitors.^19-22 Proposed ADS definitions differ somewhat, but essentially 3 features guide the diagnosis:

• appearance of characteristic symptoms (Table 2)^21,23
• timing of those symptoms, which usually emerge within 1 week of abrupt cessation or marked reduction of the antidepressant
• symptoms generally are mild, short-lived, self-limiting, and/or rapidly reversed by restarting the original antidepressant.

Evidence suggests shorter half-life antidepressants may be associated with the highest risk for ADS, but other risk factors remain presumptive (Table 3).

Table 1

FINISH: Symptoms of antidepressant discontinuation syndrome

Table 2

ADS symptoms can range across a variety of system clusters

Table 3

Possible patient risk factors for developing ADS*

What causes ADS?

Although the exact cause of ADS is unknown, the literature proposes several theories.

Because of the central serotonin system’s complex connections, acute reduction in synaptic serotonin when an SSRI or SNRI is abruptly or too quickly stopped may be the first in a cascade of steps affecting transmission of multiple monoamines. Parallels have been drawn between the phenomenon observed with rapid depletion of tryptophan—the essential amino acid precursor for the synthesis of 5-HT—and ADS seen with abrupt discontinuation of serotonergic antidepressants. This suggests that acute drops in neurotransmitter levels can precipitate neuropsychiatric and somatic manifestations of ADS.²⁴

Patients’ uncomfortable symptoms likely are caused by the serotonin, norepinephrine, and cholinergic systems and their complex interactions.²⁵ Individual genetic factors may influence patients’ vulnerability for ADS.

Managing ADS

Awareness and prevention. ADS can be misinterpreted as side effects of newly started treatment after an antidepressant is stopped. In Mr. J’s case, the appearance of muscle aches, headaches, and other ADS symptoms after ECT was started easily could have been perceived as adverse effects of ECT. Mr. J’s agitation and increased suicidal ideation could lead a clinician to mistakenly think that MDE was worsening because the antidepressant was stopped before ECT became effective. Being aware of ADS can prevent misdiagnosis and allow you to quickly identify the condition, manage the reversible syndrome, and continue with new treatment plan—in this case, ECT.

You can help prevent ADS by educating patients about the need to adhere to antidepressant regimens and to avoid missing doses. Consider ADS risk factors—particularly medications’ half-lives—before you start, change, or stop antidepressant therapy. Gradually taper all antidepressants being discontinued, with the possible exception of fluoxetine (which, including its active metabolite, has an elimination half-life of approximately 1 to 2 weeks).

Tapering antidepressants is more art than science because we have no controlled data to support any particular tapering regimen. Tailor the taper duration based on each patient’s response to sequential dosage reductions. Antidepressants with shorter half-lives—such as venlafaxine or paroxetine—may need to be tapered more slowly, perhaps by reducing the dosage by 25% every 4 to 6 weeks. If you plan to switch medications, this process may be expedited during a cross-taper to another antidepressant. You still may see discontinuation symptoms, however, depending on which new agent is chosen and which is being stopped.

Treating ADS. Appropriately recognizing ADS risk and slowly tapering antidepressants as needed usually prevents clinically significant distress associated with discontinuation. For some patients, however, ADS may be particularly severe or prolonged, or may emerge at the end of a slow taper.

Challenging cases may be more likely with paroxetine or venlafaxine—even the extended-release or controlled-release preparations. The elimination half-life of paroxetine is 15 to 20 hours, and the half-lives of venlafaxine and venlafaxine XR are 5 to 11 hours. Desvenlafaxine’s half-life is 11 hours, and product labeling of this enantiomer of racemic venlafaxine notes that discontinuation symptoms have occurred.²⁶ ADS treatment depends on the severity of the reaction and whether or not further antidepressant therapy is necessary.

For mild ADS, reassurance and treatment focused on specific symptoms—such as sedative-hypnotics for insomnia or benzodiazepines for anxiety—may be all that is needed, because ADS tends to gradually resolve over an average of 10 days.²⁷

For more severe ADS, or when ongoing antidepressant therapy is indicated, restarting the recently withdrawn antidepressant at the pre-ADS dosage typically resolves the syndrome within 24 hours. Then employ a slower, more cautious taper when next attempting to discontinue that antidepressant.

Another option. An alternate management strategy is to substitute fluoxetine to suppress ADS associated with shorter half-life SSRIs or SNRIs. Case reports^18,20,28 suggest that fluoxetine, 5 to 20 mg/d, can be used to ameliorate venlafaxine-induced ADS. Fluoxetine can be tried as monotherapy for 1 to 2 weeks and then rapidly tapered or stopped. Others have suggested combination therapy, such as:

• restarting venlafaxine at the pre-ADS dose plus fluoxetine, 20 mg/d
• tapering venlafaxine by 50% every 5 days until stopped
• reducing fluoxetine 1 week later to 10 mg/d for 5 days
• then stopping fluoxetine.²⁸

In general, SSRIs should not be co-administered with SNRIs long-term because of potential additive adverse effects such as serotonin syndrome. Combining fluoxetine with an SNRI such as venlafaxine for the purpose of tapering off venlafaxine and reducing ADS risk probably is safe, however, as long as the fluoxetine dose is low (5 to 20 mg) and SNRI reduction begins immediately, with a plan for complete tapering.

CASE CONTINUED: ECT treatment proceeds

Venlafaxine XR is not restarted to address Mr. J’s suspected ADS because of concerns about potential increased risk for cardiac events (asystole, prolonged bradycardia) during ECT with concomitant venlafaxine use.^29,30 Fluoxetine, which rarely may prolong ECT-induced seizures, is deemed a safer choice and is started immediately at 20 mg/d.

Because of Mr. J’s other symptoms, we prescribe lorazepam, 0.5 mg bid, for anxiety for 2 days; increase aripiprazole to 5 mg bid for agitation; and add zolpidem, 10 mg at bedtime, for insomnia. The following day, Mr. J reports substantial relief from ADS symptoms, including myalgias, paresthesias, and suicidal ideation.^21,23

His second ECT treatment is administered the next day, followed by a successful course of 9 treatments and partial remission of the MDE within 3 weeks. Fluoxetine is reduced to 10 mg/d one week into the ECT series, then discontinued one week later. No signs of emergent ADS are seen at discharge or 2-week outpatient follow-up. Mr. J achieves full remission with maintenance ECT plus bedtime doses of mirtazapine, 30 mg, and aripiprazole, 7.5 mg, across 6 months of follow-up care.

Related resources

• Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(suppl 4):27-30.
• American Family Physician. Patient handout on antidepressant discontinuation. www.aafp.org/afp/2006/0801/p457.html.
• Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77-87. See appendix for discontinuation-emergent signs and symptoms checklist.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Clomipramine • Anafranil
• Desvenlafaxine • Pristiq
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor
• Venlafaxine extended-release • Effexor XR
• Zolpidem • Ambien

Disclosure

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

Acknowledgment

When Dr. Muzina submitted this article to Current Psychiatry, he was director, Center for Mood Disorders Treatment and Research, Cleveland Clinic Neurological Institute, Cleveland, OH.

Discuss this article

Most psychiatrists have encountered patients who report distressing symptoms when they have forgotten to take their antidepressant for a few days or during changes in the medication regimen. A discontinuation syndrome can occur with almost any antidepressant, highlighting the need to slowly taper these medications when discontinuation is part of a treatment plan.

This article discusses antidepressant discontinuation syndrome (ADS) in a patient who experienced substantial distress after a rapid antidepressant taper in preparation for electroconvulsive therapy (ECT). My goal is to raise awareness of ADS, promote early detection of the syndrome, and address proper prevention and management strategies.

CASE REPORT: Feeling ‘worse than ever’

Mr. J, a 32-year-old tax accountant, is hospitalized for a major depressive episode (MDE) associated with deteriorating function and suicidal ideation. This second lifetime MDE started 8 months before his admission to an inpatient mood disorders unit.

Mr. J initially was treated with fluoxetine, up to 40 mg/d across 14 weeks, with good tolerability but no significant benefit. His psychiatrist switched Mr. J to bupropion but stopped it after 4 weeks because of side effects—including headaches, insomnia, and tremor—and limited antidepressant benefit. Venlafaxine XR was initiated next, at 150 mg/d within the first 2 weeks, increased to 225 mg/d at week 6, then titrated to 300 mg/d at week 10. After 10 weeks, aripiprazole, 5 mg/d, was added because Mr. J showed only partial, limited response to venlafaxine XR and this antipsychotic is indicated for adjunctive treatment of major depressive disorder.

Mr. J reported mild, transient restlessness but otherwise he tolerated the medications well, and he claimed excellent adherence. After 6 additional weeks of treatment, however, Mr. J was hospitalized because of persistent severely depressed mood, increasing suicidal ideation, and inability to function at work.

On admission, Mr. J is evaluated and agrees to ECT. To meet the ECT service’s protocol, venlafaxine XR is reduced to 150 mg/d for 2 days and then stopped when ECT is started. Aripiprazole is continued at 5 mg/d.

Mr. J tolerates the first ECT treatment well, but the morning before his second treatment he complains of feeling “worse than ever.” An agitated Mr. J reports dramatically intensified suicidal ideation—much more intrusive than before he was hospitalized. He also complains of diffuse muscle aches and cramps, runny nose, nausea, headache, and burning sensations in both arms and hands. He withdraws consent for ECT and returns to the mood disorders unit for ongoing treatment.

Could this be ADS?

Yes, it could. In this case, the inpatient psychiatrist and treatment team were lulled into a false sense of security by Mr. J’s history of few side effects with various treatments and medication changes. The ECT service wanted the patient off venlafaxine XR before beginning ECT, and the treatment team believed a quick taper would not cause discontinuation symptoms because Mr. J was taking an “extended-release” medication.

Within 72 hours, Mr. J went from taking 300 mg/d of venlafaxine XR to none. Within 2 days of cessation, he complained of symptoms that could characterize a discontinuation syndrome. A potential red herring in this case is that the patient complained of feeling worse after his first ECT treatment, and one might erroneously think the myalgias, headache, and other somatic symptoms were side effects of ECT and/or anesthesia.

Typical ADS symptoms

Nearly all antidepressant classes are associated with ADS. Symptoms vary from patient to patient but typically include the “FINISH” syndrome: flu-like symptoms, ###bold/bold###nsomnia, nausea, ###bold/bold###mbalance, sensory disturbances, and hyperarousal (anxiety/agitation) (Table 1).¹

Adverse effects after stopping tricyclic antidepressants have been well documented. They may include FINISH syndrome features as well as cholinergic overdrive or “rebound” such as abdominal cramping and diarrhea.^2-4 Reports of ADS after patients stopped selective serotonin reuptake inhibitors (SSRIs) emerged soon after these agents were introduced.^5-7 Similarly, ADS has been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine,^8-10 venlafaxine XR,¹¹ and duloxetine.¹² ADS symptoms are similar with SSRIs and SNRIs, generally without the anticholinergic effects associated with tricyclic antidepressant discontinuation.

Fewer reports of discontinuation syndrome exist for bupropion, mirtazapine, monoamine oxidase inhibitors (MAOIs), and nefazodone.^13-17 Discontinuation-emergent syndromes with these non-SSRI/non-SNRI antidepressants tend to present differently. With MAOIs, for example, neuropsychiatric symptoms such as severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, delirium, and paranoid psychosis can be prominent.¹⁷

The prevalence of ADS is unclear, and published estimates vary widely because of the lack of large controlled studies. ADS rates with SSRIs/SNRIs have been reported from as low as 0% for fluoxetine to higher rates for shorter half-life antidepressants:

• 2.2% with sertraline
• 14% with fluvoxamine
• 20% with paroxetine
• 30.8% with clomipramine.

These rates come from a retrospective case note review of patients who discontinued antidepressants under supervision.¹⁸ In a small cohort of outpatients being treated for major depressive disorder, stopping venlafaxine XR was associated with discontinuation symptoms for the next 3 days in 7 of 9 patients (78%), compared with 2 of 9 patients (22%) stopping placebo.¹¹

Diagnostic criteria have been proposed for ADS associated with serotonin (5-HT) reuptake inhibitors.^19-22 Proposed ADS definitions differ somewhat, but essentially 3 features guide the diagnosis:

• appearance of characteristic symptoms (Table 2)^21,23
• timing of those symptoms, which usually emerge within 1 week of abrupt cessation or marked reduction of the antidepressant
• symptoms generally are mild, short-lived, self-limiting, and/or rapidly reversed by restarting the original antidepressant.

Evidence suggests shorter half-life antidepressants may be associated with the highest risk for ADS, but other risk factors remain presumptive (Table 3).

Table 1

FINISH: Symptoms of antidepressant discontinuation syndrome

Table 2

ADS symptoms can range across a variety of system clusters

Table 3

Possible patient risk factors for developing ADS*

What causes ADS?

Although the exact cause of ADS is unknown, the literature proposes several theories.

Because of the central serotonin system’s complex connections, acute reduction in synaptic serotonin when an SSRI or SNRI is abruptly or too quickly stopped may be the first in a cascade of steps affecting transmission of multiple monoamines. Parallels have been drawn between the phenomenon observed with rapid depletion of tryptophan—the essential amino acid precursor for the synthesis of 5-HT—and ADS seen with abrupt discontinuation of serotonergic antidepressants. This suggests that acute drops in neurotransmitter levels can precipitate neuropsychiatric and somatic manifestations of ADS.²⁴

Patients’ uncomfortable symptoms likely are caused by the serotonin, norepinephrine, and cholinergic systems and their complex interactions.²⁵ Individual genetic factors may influence patients’ vulnerability for ADS.

Managing ADS

Awareness and prevention. ADS can be misinterpreted as side effects of newly started treatment after an antidepressant is stopped. In Mr. J’s case, the appearance of muscle aches, headaches, and other ADS symptoms after ECT was started easily could have been perceived as adverse effects of ECT. Mr. J’s agitation and increased suicidal ideation could lead a clinician to mistakenly think that MDE was worsening because the antidepressant was stopped before ECT became effective. Being aware of ADS can prevent misdiagnosis and allow you to quickly identify the condition, manage the reversible syndrome, and continue with new treatment plan—in this case, ECT.

You can help prevent ADS by educating patients about the need to adhere to antidepressant regimens and to avoid missing doses. Consider ADS risk factors—particularly medications’ half-lives—before you start, change, or stop antidepressant therapy. Gradually taper all antidepressants being discontinued, with the possible exception of fluoxetine (which, including its active metabolite, has an elimination half-life of approximately 1 to 2 weeks).

Tapering antidepressants is more art than science because we have no controlled data to support any particular tapering regimen. Tailor the taper duration based on each patient’s response to sequential dosage reductions. Antidepressants with shorter half-lives—such as venlafaxine or paroxetine—may need to be tapered more slowly, perhaps by reducing the dosage by 25% every 4 to 6 weeks. If you plan to switch medications, this process may be expedited during a cross-taper to another antidepressant. You still may see discontinuation symptoms, however, depending on which new agent is chosen and which is being stopped.

Treating ADS. Appropriately recognizing ADS risk and slowly tapering antidepressants as needed usually prevents clinically significant distress associated with discontinuation. For some patients, however, ADS may be particularly severe or prolonged, or may emerge at the end of a slow taper.

Challenging cases may be more likely with paroxetine or venlafaxine—even the extended-release or controlled-release preparations. The elimination half-life of paroxetine is 15 to 20 hours, and the half-lives of venlafaxine and venlafaxine XR are 5 to 11 hours. Desvenlafaxine’s half-life is 11 hours, and product labeling of this enantiomer of racemic venlafaxine notes that discontinuation symptoms have occurred.²⁶ ADS treatment depends on the severity of the reaction and whether or not further antidepressant therapy is necessary.

For mild ADS, reassurance and treatment focused on specific symptoms—such as sedative-hypnotics for insomnia or benzodiazepines for anxiety—may be all that is needed, because ADS tends to gradually resolve over an average of 10 days.²⁷

For more severe ADS, or when ongoing antidepressant therapy is indicated, restarting the recently withdrawn antidepressant at the pre-ADS dosage typically resolves the syndrome within 24 hours. Then employ a slower, more cautious taper when next attempting to discontinue that antidepressant.

Another option. An alternate management strategy is to substitute fluoxetine to suppress ADS associated with shorter half-life SSRIs or SNRIs. Case reports^18,20,28 suggest that fluoxetine, 5 to 20 mg/d, can be used to ameliorate venlafaxine-induced ADS. Fluoxetine can be tried as monotherapy for 1 to 2 weeks and then rapidly tapered or stopped. Others have suggested combination therapy, such as:

• restarting venlafaxine at the pre-ADS dose plus fluoxetine, 20 mg/d
• tapering venlafaxine by 50% every 5 days until stopped
• reducing fluoxetine 1 week later to 10 mg/d for 5 days
• then stopping fluoxetine.²⁸

In general, SSRIs should not be co-administered with SNRIs long-term because of potential additive adverse effects such as serotonin syndrome. Combining fluoxetine with an SNRI such as venlafaxine for the purpose of tapering off venlafaxine and reducing ADS risk probably is safe, however, as long as the fluoxetine dose is low (5 to 20 mg) and SNRI reduction begins immediately, with a plan for complete tapering.

CASE CONTINUED: ECT treatment proceeds

Venlafaxine XR is not restarted to address Mr. J’s suspected ADS because of concerns about potential increased risk for cardiac events (asystole, prolonged bradycardia) during ECT with concomitant venlafaxine use.^29,30 Fluoxetine, which rarely may prolong ECT-induced seizures, is deemed a safer choice and is started immediately at 20 mg/d.

Because of Mr. J’s other symptoms, we prescribe lorazepam, 0.5 mg bid, for anxiety for 2 days; increase aripiprazole to 5 mg bid for agitation; and add zolpidem, 10 mg at bedtime, for insomnia. The following day, Mr. J reports substantial relief from ADS symptoms, including myalgias, paresthesias, and suicidal ideation.^21,23

His second ECT treatment is administered the next day, followed by a successful course of 9 treatments and partial remission of the MDE within 3 weeks. Fluoxetine is reduced to 10 mg/d one week into the ECT series, then discontinued one week later. No signs of emergent ADS are seen at discharge or 2-week outpatient follow-up. Mr. J achieves full remission with maintenance ECT plus bedtime doses of mirtazapine, 30 mg, and aripiprazole, 7.5 mg, across 6 months of follow-up care.

Related resources

• Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(suppl 4):27-30.
• American Family Physician. Patient handout on antidepressant discontinuation. www.aafp.org/afp/2006/0801/p457.html.
• Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77-87. See appendix for discontinuation-emergent signs and symptoms checklist.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Clomipramine • Anafranil
• Desvenlafaxine • Pristiq
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor
• Venlafaxine extended-release • Effexor XR
• Zolpidem • Ambien

Disclosure

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

Acknowledgment

When Dr. Muzina submitted this article to Current Psychiatry, he was director, Center for Mood Disorders Treatment and Research, Cleveland Clinic Neurological Institute, Cleveland, OH.

Dr. I, a 48-year-old university professor, is brought to the ER by her husband because she has developed an irrational fear of being chased by Nazis. The fears have become increasingly bizarre, her husband reports. She believes her Nazi persecutors are bandaging their arms and using wheelchairs to pretend to be disabled. When out with her husband, Dr. I points to people in wheelchairs, convinced they are after her, will kill her, and are incensed because she left Germany—her country of birth. Her hus­band brought her to the ER when she started to hear her persecutors addressing her in German at night.

Psychoses of unknown cause usually begin in late ado­lescence or early adulthood. Less frequently the onset occurs in later adulthood (age ≥40). Late-onset psycho­sis is much more prevalent in women than in men for reasons that are imperfectly understood.

When you are evaluating a midlife woman with first onset of psychosis, don’t assume an illness of unknown cause (bipolar disorder or schizophrenia) until after you have done a comprehensive search for triggers of her psychotic symptoms. After age 40, women are more likely than men to develop psychosis because of gender-specific medical and psychological precipitants.

Predisposing factors for psychosis
Psychosis is an emergent quality of structural and chemical changes in the brain. As such, it can be ex­pected to surface during:
   • brain reorganization or transition (adolescence, senescence, brain trauma, stroke, starvation, inflammation, or brain tumor)
   • change in brain chemistry (flux in go­nadal, thyroid, or adrenal hormone levels; electrolyte imbalance; fever; exposure to chemical substances; immune response).

Psychological stress impacting the brain via stress hormones also can predispose a person to psychosis.

Because some individuals are more prone than others to develop psycho­sis during brain alteration, chemical and structural changes in the brain are as­sumed to interact with genetic propensi­ties to influence gene expression. Once a psychotic event has occurred, it is thought to sensitize the brain so that subsequent events emerge more readily.¹

Schizophrenia—though not the only ill­ness in which psychosis plays a role—is a prototype for psychotic illness, and sev­eral reported sex differences in this dis­order are worth noting.² The incidence of schizophrenia is approximately the same in both sexes, but women show a later age of onset—a paradox in that the brain de­velops at a faster pace in females and theo­retically should reach the threshold for the first appearance of schizophrenia earlier. Women also require lower doses of anti­psychotic medication to recover from an acute psychotic episode and to maintain remission, at least before menopause.^3,4 Both of these differences can be explained as an effect of estrogen on a) gene expres­sion⁵ and b) liver enzymes that metabolize antipsychotics.⁶

The estrogen hypothesis. Women show a tendency toward premenstrual and post­partum exacerbation of symptoms when estrogen levels are relatively low. These clinical observations, confirmed by some but not all studies, have led to the hypoth­esis that estrogens are neuroprotective⁷ and also protect against psychosis.⁸

Estrogen withdrawal in specific brain cells may release a cascade of events that over time can increase the severity of psy­chotic and cognitive symptoms. The reason for suspecting such effects is based on what we know about estrogenic effects on neurotransmitter, cognitive, and stress-induction pathways, and—more fundamentally—on neuronal growth and atrophy.

According to the estrogen hypothesis, women are—to some degree—protected against schizophrenia by their relatively high gonadal estrogen production between puberty and and menopause. Women lose this protection with the onset of perimeno­pausal estrogen fluctuation and decline, accounting for their second peak of illness onset after age 45.

Epidemiologic studies showing a second peak of schizophrenia onset in women (but not men) around the age of menopause sup­port this hypothesis.^9,10 Longitudinal out­comes for schizophrenia—which are better in women than in men during late adolescence or early adulthood11—gradually even out after the first 15 years of illness, suggest­ing that women’s advantage is lost at a time approximating menopause (Box 1).

The question, then, becomes: Is it only because of estrogen loss after age 40 that women become more prone to develop a psychotic illness? Other differences be­tween the sexes that may play roles include immune function, low iron stores, sleep suf­ficiency, thyroid function, exposure to toxic substances (including therapeutic drugs), societal pressures to be slim while aging (Table), and the experience of stress.¹²

CASE CONTINUED
Exhausted and confused
Dr. I is a well-groomed, handsome woman, but she hardly speaks when interviewed, looking frightened and somewhat bewildered. She has never had a mental health problem, nor has anyone in her family. She agrees to stay in the hospital but is not sure why. She has slept no more than 1 or 2 hours in the last several days.

Her early history is unremarkable. She did well in school. After earning a PhD at the Univer­sity of Leipzig, she and her husband immigrated to Canada. Both are university professors. They never decided not to have children, but children hadn’t come. Her menstrual periods stopped 2 years before admission. The question about children is the only 1 that elicits emotion in Dr. I. When I ask about it, tears come to her eyes as she shakes her head.

Her husband reports that she has not been eating well and has, in the last year, started to drink more alcohol than usual—3 to 4 drinks of whiskey a night. She does not smoke cigarettes, and her health generally is good. She uses no medications. Her hus­band describes their marital relationship as very close, although it has become strained in recent weeks because of her unreasonable fears. He admits that their work is always stressful; competition is fierce, with more and more deadlines and less and less leisure time. The couple has few friends and no hobbies.

Late-onset psychosis symptoms
In late-onset psychosis (after age 45), men appear to suffer substantially milder symp­toms and spend less time hospitalized than women.¹³ Women with late-onset schizophrenia have more severe positive symptoms than men and fewer negative symptoms.^14,15 Overall, patients with late-onset schizophrenia have a lower prevalence of looseness of associations and negative symptoms than those with earlier onset.^16,17

In addition, individuals with schizo­phrenia who become ill in middle age have been reported to:
   • show better neuropsychological per­formance (particularly in learning and ab­straction/cognitive flexibility) than those with early onset
   • possibly have larger thalamic volumes
   • respond to lower antipsychotic doses.¹⁸

Auditory and visual hallucinations frequently are observed in patients with comorbid late-onset schizophrenia and auditory and visual impairment.¹⁶ Palmer et al¹⁸ reported no difference in family his­tory of schizophrenia between early and late onset, but this is controversial. Con­vert et al¹⁶ note that most studies reveal a lower lifetime risk of schizophrenia in first-degree relatives of patients with late-onset than early-onset schizophrenia.

CASE CONTINUED
Medical workup
Dr. I’s physical exam is unremarkable. Her thy­roid is not enlarged; there are no breast lumps. On mental status exam, her mood is flat. She is preoccupied with fears of the Nazis. Routine blood tests show slight anemia; fasting glu­cose levels are within normal range.

I give Dr. I zopiclone, 7.5 mg, to help her sleep. The next day she keeps to herself, eats very little, and appears disinterested in her surroundings. Nursing staff report that she often seems frightened. Dr. I asks to use the ward phone to call Germany but is told that she cannot make long distance calls from that phone. This seems to disturb her.

Differential diagnosis
Sensory impairment, substance abuse, and metabolic changes have been implicated in the appearance of psychosis in later life. More specific to women than men, howev­er, are medical and psychiatric precipitants. These include autoimmune disease (and its treatment) and psychiatric disorders, as well as thyroid dysfunction, self-induced starvation (anorexia nervosa) and diet aids, substance use and abuse, insomnia, and iron deficiency (Table).

Autoimmune disease and treatment. Nearly 80% of patients with autoimmune disease are women, and these disorders (as well as their treatment) can manifest as psychosis. Corticosteroids have a well-documented history of triggering psy­chotic symptoms, which are twice as likely in women than in men. The incidence of severe psychosis while taking oral predni­sone ranges from 1.6% to 50% and averages 5.7%. The average daily dose of corticoste­roids for patients who develop psychosis is 59.5 mg/d.

Corticosteroid creams absorbed through skin as well as inhaled and intranasal cor­ticosteroids in their more potent formula­tions can have systemic effects, including psychosis. Nonsteroidal anti-inflammatory drugs such as ibuprofen also can trigger psychosis.¹⁹

Psychiatric disorders. Posttraumatic stress disorder with psychotic symptoms may overlap with categories such as psy­chogenic psychoses, hysterical psychoses, nonaffective remitting psychoses, acute brief psychoses, reactive psychoses, acute and transient psychoses, and bouffées dé­lirantes (in France, the name for transient psychotic reactions).²⁰ Consider these female-predominant conditions in the differential diagnosis, along with micro­psychotic episodes in borderline personal­ity disorder, in which the predominance of women is 3:1.

Medical treatment for depression and anxiety also can lead to psychotic symp­toms through individual susceptibility to the action of specific drugs or through withdrawal effects.

Clinical assessment
Question all women presenting with psy­chosis about eating habits and diet pills, and check for hypokalemia and hypocal­cemia to rule out starvation effects and reactions to stimulants. Also ask about in­halants, and examine for anemia and thy­roid dysfunction. Consider all medications as having the potential to trigger psychotic symptoms.

A family history of illness is important, with a focus on autoimmune disorder and its treatment. A thorough psychiatric history is crucial and needs to include assess­ment of sleep, mood, and relationships with attachment figures. Do not assume ill­nesses of unknown cause (bipolar disorder or schizophrenia) until after a comprehen­sive search for precipitants of psychotic symptoms.

CASE CONTINUED
Guilty feelings
To address her delusions, I start Dr. I on ris­peridone, 2 mg at bedtime. She goes home for the weekend, and her husband reports that she slept throughout the visit. When she returns, she spends a lot of time in bed but is more communicative.

When I ask Dr. I whether she has called Germany, she says she called her recently widowed father. Dr. I begins to cry when talk­ing of her mother, and tells the nurse she feels guilty for not visiting for the last few years. When her mother died 6 months ago, Dr. I had not seen her in 4 years.

Her fears remit with risperidone, main­tained at 2 mg/d, but Dr. I remains depressed and responds slowly to treatment with cital­opram, 20 mg/d, and supportive therapy. Her final diagnosis is mood disorder with psy­chotic features.

Treatment
When treating women with late-onset psy­chosis, remove all potential triggers and address underlying illness. Cognitive ther­apy targeting specific symptoms is useful; antipsychotics probably will be necessary. Age-related physiologic changes make older persons more sensitive to the thera­peutic and toxic effects of antipsychotics.

Estrogen therapy? Women suffering from schizophrenia show significantly lower es­trogen levels than the general population of women, and they experience first-onset or recurrence of a psychotic episode signif­icantly more often in low estrogen phases of the cycle. Estrogens have therefore been postulated to constitute a protective factor against psychosis, which means perimeno­pause is an at-risk period.²¹ Although evi­dence is limited, preliminary studies have found beneficial effects from short-term, off-label use of estrogen therapy in women with psychotic illness (Box 2).

Because continuous use of estrogen plus progestin has been associated with an in­creased risk of adverse effects,²² off-label use of selective estrogen receptor modula­tors (SERMs) also is being investigated in women with schizophrenia. SERMs act as tissue-specific estrogen agonists and an­tagonists because they can either inhibit or enhance estrogen-induced activation of estrogen response element-containing genes.²³

Wong et al²⁴ used a crossover design to compare the SERM raloxifene with place­bo as adjunctive treatment for 6 postmeno­pausal women with schizophrenia. Each woman received 8 weeks of raloxifene, 60 mg/d, and 8 weeks of placebo. Three be­gan with placebo and 3 with raloxifene.

Verbal memory was measured weekly with the California Verbal Learning Test, using 5 memory trials, free and cued short-delay recall, and long-delay recall. At baseline, the participants had lower scores than older adults in the general popula­tion. Eight weeks of placebo improved scores somewhat, suggesting a practice effect. Eight weeks of raloxifene improved cognitive scores to a level similar to that of schizophrenia-free subjects. After 16 weeks, however, cognitive scores in the 2 groups were indistinguishable.

At present I do not recommend estrogen for women with late-onset schizophrenia because the risk is too high and raloxifene does not enter the brain sufficiently to be a valuable cognitive enhancer. Novel SERMs with more specific efficacy for improving cognitive function may prove useful in the future,²⁵ however, as may phytoestro­gens. Adjunctive hormone modulation is a promising area of gender-specific treat­ment for serious mental illness.²⁶

CASE CONCLUSION
Gradually improving
Dr. I’s depression was triggered by her moth­er’s death and regrets about not visiting and not being a mother. The content of her de­lusions was related to her guilt about not having returned to Germany; the delusions were probably triggered by depression, al­cohol intake, her relative hypoestrogenic state, stress at work, lack of social supports, and dependence on her husband.

Over the next few years, Dr. I is maintained on a low dose of risperidone (reduced from 2 mg/d to 1 mg/d) and citalopram (reduced from 20 mg/d to 10 mg/d). She becomes increas­ingly engaged in supportive dynamic therapy, and her symptoms gradually improve.

BOTTOM LINE
Psychosis onset in midlife is mostly a female phenomenon because a perimenopausal estrogen decline increases women’s susceptibility. Seek specific triggers such as medical illness or response to a drug before assuming an illness of unknown cause such as bipolar disorder or schizophrenia. Cognitive therapy targeting specific symptoms is useful; antipsychotics probably will be necessary.

Related Resources
• Women and psychosis: A guide for women and their families. Centre for Addiction and Mental Health. University of Toronto. www.camh.net/About_Addiction_Mental_ Health/Mental_Health_Information/Women_Psychosis.
• Seeman MV. Women and psychosis. www.medscape.com/ viewarticle/408912.
• Chattopadhyay S. Estrogen and schizophrenia: Any link? The Internet Journal of Mental Health. 2004;2(1). www.ispub. com/journal/the_internet_journal_of_mental_health.html.

Drug Brand Names
Citalopram • Celexa                         Prednisone • Deltasone,
Estradiol • Estrace,                                    Orasone, others
   Estrofem, others                           Raloxifene • Evista
Estradiol transdermal •                     Risperidone • Risperdal
   Estraderm , Climara, others
Methylphenidate • Concerta,
   Ritalin, others

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

Dr. I, a 48-year-old university professor, is brought to the ER by her husband because she has developed an irrational fear of being chased by Nazis. The fears have become increasingly bizarre, her husband reports. She believes her Nazi persecutors are bandaging their arms and using wheelchairs to pretend to be disabled. When out with her husband, Dr. I points to people in wheelchairs, convinced they are after her, will kill her, and are incensed because she left Germany—her country of birth. Her hus­band brought her to the ER when she started to hear her persecutors addressing her in German at night.

Psychoses of unknown cause usually begin in late ado­lescence or early adulthood. Less frequently the onset occurs in later adulthood (age ≥40). Late-onset psycho­sis is much more prevalent in women than in men for reasons that are imperfectly understood.

When you are evaluating a midlife woman with first onset of psychosis, don’t assume an illness of unknown cause (bipolar disorder or schizophrenia) until after you have done a comprehensive search for triggers of her psychotic symptoms. After age 40, women are more likely than men to develop psychosis because of gender-specific medical and psychological precipitants.

Predisposing factors for psychosis
Psychosis is an emergent quality of structural and chemical changes in the brain. As such, it can be ex­pected to surface during:
   • brain reorganization or transition (adolescence, senescence, brain trauma, stroke, starvation, inflammation, or brain tumor)
   • change in brain chemistry (flux in go­nadal, thyroid, or adrenal hormone levels; electrolyte imbalance; fever; exposure to chemical substances; immune response).

Psychological stress impacting the brain via stress hormones also can predispose a person to psychosis.

Because some individuals are more prone than others to develop psycho­sis during brain alteration, chemical and structural changes in the brain are as­sumed to interact with genetic propensi­ties to influence gene expression. Once a psychotic event has occurred, it is thought to sensitize the brain so that subsequent events emerge more readily.¹

Schizophrenia—though not the only ill­ness in which psychosis plays a role—is a prototype for psychotic illness, and sev­eral reported sex differences in this dis­order are worth noting.² The incidence of schizophrenia is approximately the same in both sexes, but women show a later age of onset—a paradox in that the brain de­velops at a faster pace in females and theo­retically should reach the threshold for the first appearance of schizophrenia earlier. Women also require lower doses of anti­psychotic medication to recover from an acute psychotic episode and to maintain remission, at least before menopause.^3,4 Both of these differences can be explained as an effect of estrogen on a) gene expres­sion⁵ and b) liver enzymes that metabolize antipsychotics.⁶

The estrogen hypothesis. Women show a tendency toward premenstrual and post­partum exacerbation of symptoms when estrogen levels are relatively low. These clinical observations, confirmed by some but not all studies, have led to the hypoth­esis that estrogens are neuroprotective⁷ and also protect against psychosis.⁸

Estrogen withdrawal in specific brain cells may release a cascade of events that over time can increase the severity of psy­chotic and cognitive symptoms. The reason for suspecting such effects is based on what we know about estrogenic effects on neurotransmitter, cognitive, and stress-induction pathways, and—more fundamentally—on neuronal growth and atrophy.

According to the estrogen hypothesis, women are—to some degree—protected against schizophrenia by their relatively high gonadal estrogen production between puberty and and menopause. Women lose this protection with the onset of perimeno­pausal estrogen fluctuation and decline, accounting for their second peak of illness onset after age 45.

Epidemiologic studies showing a second peak of schizophrenia onset in women (but not men) around the age of menopause sup­port this hypothesis.^9,10 Longitudinal out­comes for schizophrenia—which are better in women than in men during late adolescence or early adulthood11—gradually even out after the first 15 years of illness, suggest­ing that women’s advantage is lost at a time approximating menopause (Box 1).

The question, then, becomes: Is it only because of estrogen loss after age 40 that women become more prone to develop a psychotic illness? Other differences be­tween the sexes that may play roles include immune function, low iron stores, sleep suf­ficiency, thyroid function, exposure to toxic substances (including therapeutic drugs), societal pressures to be slim while aging (Table), and the experience of stress.¹²

CASE CONTINUED
Exhausted and confused
Dr. I is a well-groomed, handsome woman, but she hardly speaks when interviewed, looking frightened and somewhat bewildered. She has never had a mental health problem, nor has anyone in her family. She agrees to stay in the hospital but is not sure why. She has slept no more than 1 or 2 hours in the last several days.

Her early history is unremarkable. She did well in school. After earning a PhD at the Univer­sity of Leipzig, she and her husband immigrated to Canada. Both are university professors. They never decided not to have children, but children hadn’t come. Her menstrual periods stopped 2 years before admission. The question about children is the only 1 that elicits emotion in Dr. I. When I ask about it, tears come to her eyes as she shakes her head.

Her husband reports that she has not been eating well and has, in the last year, started to drink more alcohol than usual—3 to 4 drinks of whiskey a night. She does not smoke cigarettes, and her health generally is good. She uses no medications. Her hus­band describes their marital relationship as very close, although it has become strained in recent weeks because of her unreasonable fears. He admits that their work is always stressful; competition is fierce, with more and more deadlines and less and less leisure time. The couple has few friends and no hobbies.

Late-onset psychosis symptoms
In late-onset psychosis (after age 45), men appear to suffer substantially milder symp­toms and spend less time hospitalized than women.¹³ Women with late-onset schizophrenia have more severe positive symptoms than men and fewer negative symptoms.^14,15 Overall, patients with late-onset schizophrenia have a lower prevalence of looseness of associations and negative symptoms than those with earlier onset.^16,17

In addition, individuals with schizo­phrenia who become ill in middle age have been reported to:
   • show better neuropsychological per­formance (particularly in learning and ab­straction/cognitive flexibility) than those with early onset
   • possibly have larger thalamic volumes
   • respond to lower antipsychotic doses.¹⁸

Auditory and visual hallucinations frequently are observed in patients with comorbid late-onset schizophrenia and auditory and visual impairment.¹⁶ Palmer et al¹⁸ reported no difference in family his­tory of schizophrenia between early and late onset, but this is controversial. Con­vert et al¹⁶ note that most studies reveal a lower lifetime risk of schizophrenia in first-degree relatives of patients with late-onset than early-onset schizophrenia.

CASE CONTINUED
Medical workup
Dr. I’s physical exam is unremarkable. Her thy­roid is not enlarged; there are no breast lumps. On mental status exam, her mood is flat. She is preoccupied with fears of the Nazis. Routine blood tests show slight anemia; fasting glu­cose levels are within normal range.

I give Dr. I zopiclone, 7.5 mg, to help her sleep. The next day she keeps to herself, eats very little, and appears disinterested in her surroundings. Nursing staff report that she often seems frightened. Dr. I asks to use the ward phone to call Germany but is told that she cannot make long distance calls from that phone. This seems to disturb her.

Differential diagnosis
Sensory impairment, substance abuse, and metabolic changes have been implicated in the appearance of psychosis in later life. More specific to women than men, howev­er, are medical and psychiatric precipitants. These include autoimmune disease (and its treatment) and psychiatric disorders, as well as thyroid dysfunction, self-induced starvation (anorexia nervosa) and diet aids, substance use and abuse, insomnia, and iron deficiency (Table).

Autoimmune disease and treatment. Nearly 80% of patients with autoimmune disease are women, and these disorders (as well as their treatment) can manifest as psychosis. Corticosteroids have a well-documented history of triggering psy­chotic symptoms, which are twice as likely in women than in men. The incidence of severe psychosis while taking oral predni­sone ranges from 1.6% to 50% and averages 5.7%. The average daily dose of corticoste­roids for patients who develop psychosis is 59.5 mg/d.

Corticosteroid creams absorbed through skin as well as inhaled and intranasal cor­ticosteroids in their more potent formula­tions can have systemic effects, including psychosis. Nonsteroidal anti-inflammatory drugs such as ibuprofen also can trigger psychosis.¹⁹

Psychiatric disorders. Posttraumatic stress disorder with psychotic symptoms may overlap with categories such as psy­chogenic psychoses, hysterical psychoses, nonaffective remitting psychoses, acute brief psychoses, reactive psychoses, acute and transient psychoses, and bouffées dé­lirantes (in France, the name for transient psychotic reactions).²⁰ Consider these female-predominant conditions in the differential diagnosis, along with micro­psychotic episodes in borderline personal­ity disorder, in which the predominance of women is 3:1.

Medical treatment for depression and anxiety also can lead to psychotic symp­toms through individual susceptibility to the action of specific drugs or through withdrawal effects.

Clinical assessment
Question all women presenting with psy­chosis about eating habits and diet pills, and check for hypokalemia and hypocal­cemia to rule out starvation effects and reactions to stimulants. Also ask about in­halants, and examine for anemia and thy­roid dysfunction. Consider all medications as having the potential to trigger psychotic symptoms.

A family history of illness is important, with a focus on autoimmune disorder and its treatment. A thorough psychiatric history is crucial and needs to include assess­ment of sleep, mood, and relationships with attachment figures. Do not assume ill­nesses of unknown cause (bipolar disorder or schizophrenia) until after a comprehen­sive search for precipitants of psychotic symptoms.

CASE CONTINUED
Guilty feelings
To address her delusions, I start Dr. I on ris­peridone, 2 mg at bedtime. She goes home for the weekend, and her husband reports that she slept throughout the visit. When she returns, she spends a lot of time in bed but is more communicative.

When I ask Dr. I whether she has called Germany, she says she called her recently widowed father. Dr. I begins to cry when talk­ing of her mother, and tells the nurse she feels guilty for not visiting for the last few years. When her mother died 6 months ago, Dr. I had not seen her in 4 years.

Her fears remit with risperidone, main­tained at 2 mg/d, but Dr. I remains depressed and responds slowly to treatment with cital­opram, 20 mg/d, and supportive therapy. Her final diagnosis is mood disorder with psy­chotic features.

Treatment
When treating women with late-onset psy­chosis, remove all potential triggers and address underlying illness. Cognitive ther­apy targeting specific symptoms is useful; antipsychotics probably will be necessary. Age-related physiologic changes make older persons more sensitive to the thera­peutic and toxic effects of antipsychotics.

Estrogen therapy? Women suffering from schizophrenia show significantly lower es­trogen levels than the general population of women, and they experience first-onset or recurrence of a psychotic episode signif­icantly more often in low estrogen phases of the cycle. Estrogens have therefore been postulated to constitute a protective factor against psychosis, which means perimeno­pause is an at-risk period.²¹ Although evi­dence is limited, preliminary studies have found beneficial effects from short-term, off-label use of estrogen therapy in women with psychotic illness (Box 2).

Because continuous use of estrogen plus progestin has been associated with an in­creased risk of adverse effects,²² off-label use of selective estrogen receptor modula­tors (SERMs) also is being investigated in women with schizophrenia. SERMs act as tissue-specific estrogen agonists and an­tagonists because they can either inhibit or enhance estrogen-induced activation of estrogen response element-containing genes.²³

Wong et al²⁴ used a crossover design to compare the SERM raloxifene with place­bo as adjunctive treatment for 6 postmeno­pausal women with schizophrenia. Each woman received 8 weeks of raloxifene, 60 mg/d, and 8 weeks of placebo. Three be­gan with placebo and 3 with raloxifene.

Verbal memory was measured weekly with the California Verbal Learning Test, using 5 memory trials, free and cued short-delay recall, and long-delay recall. At baseline, the participants had lower scores than older adults in the general popula­tion. Eight weeks of placebo improved scores somewhat, suggesting a practice effect. Eight weeks of raloxifene improved cognitive scores to a level similar to that of schizophrenia-free subjects. After 16 weeks, however, cognitive scores in the 2 groups were indistinguishable.

At present I do not recommend estrogen for women with late-onset schizophrenia because the risk is too high and raloxifene does not enter the brain sufficiently to be a valuable cognitive enhancer. Novel SERMs with more specific efficacy for improving cognitive function may prove useful in the future,²⁵ however, as may phytoestro­gens. Adjunctive hormone modulation is a promising area of gender-specific treat­ment for serious mental illness.²⁶

CASE CONCLUSION
Gradually improving
Dr. I’s depression was triggered by her moth­er’s death and regrets about not visiting and not being a mother. The content of her de­lusions was related to her guilt about not having returned to Germany; the delusions were probably triggered by depression, al­cohol intake, her relative hypoestrogenic state, stress at work, lack of social supports, and dependence on her husband.

Over the next few years, Dr. I is maintained on a low dose of risperidone (reduced from 2 mg/d to 1 mg/d) and citalopram (reduced from 20 mg/d to 10 mg/d). She becomes increas­ingly engaged in supportive dynamic therapy, and her symptoms gradually improve.

BOTTOM LINE
Psychosis onset in midlife is mostly a female phenomenon because a perimenopausal estrogen decline increases women’s susceptibility. Seek specific triggers such as medical illness or response to a drug before assuming an illness of unknown cause such as bipolar disorder or schizophrenia. Cognitive therapy targeting specific symptoms is useful; antipsychotics probably will be necessary.

Related Resources
• Women and psychosis: A guide for women and their families. Centre for Addiction and Mental Health. University of Toronto. www.camh.net/About_Addiction_Mental_ Health/Mental_Health_Information/Women_Psychosis.
• Seeman MV. Women and psychosis. www.medscape.com/ viewarticle/408912.
• Chattopadhyay S. Estrogen and schizophrenia: Any link? The Internet Journal of Mental Health. 2004;2(1). www.ispub. com/journal/the_internet_journal_of_mental_health.html.

Drug Brand Names
Citalopram • Celexa                         Prednisone • Deltasone,
Estradiol • Estrace,                                    Orasone, others
   Estrofem, others                           Raloxifene • Evista
Estradiol transdermal •                     Risperidone • Risperdal
   Estraderm , Climara, others
Methylphenidate • Concerta,
   Ritalin, others

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

Dr. I, a 48-year-old university professor, is brought to the ER by her husband because she has developed an irrational fear of being chased by Nazis. The fears have become increasingly bizarre, her husband reports. She believes her Nazi persecutors are bandaging their arms and using wheelchairs to pretend to be disabled. When out with her husband, Dr. I points to people in wheelchairs, convinced they are after her, will kill her, and are incensed because she left Germany—her country of birth. Her hus­band brought her to the ER when she started to hear her persecutors addressing her in German at night.

Psychoses of unknown cause usually begin in late ado­lescence or early adulthood. Less frequently the onset occurs in later adulthood (age ≥40). Late-onset psycho­sis is much more prevalent in women than in men for reasons that are imperfectly understood.

When you are evaluating a midlife woman with first onset of psychosis, don’t assume an illness of unknown cause (bipolar disorder or schizophrenia) until after you have done a comprehensive search for triggers of her psychotic symptoms. After age 40, women are more likely than men to develop psychosis because of gender-specific medical and psychological precipitants.

Predisposing factors for psychosis
Psychosis is an emergent quality of structural and chemical changes in the brain. As such, it can be ex­pected to surface during:
   • brain reorganization or transition (adolescence, senescence, brain trauma, stroke, starvation, inflammation, or brain tumor)
   • change in brain chemistry (flux in go­nadal, thyroid, or adrenal hormone levels; electrolyte imbalance; fever; exposure to chemical substances; immune response).

Psychological stress impacting the brain via stress hormones also can predispose a person to psychosis.

Because some individuals are more prone than others to develop psycho­sis during brain alteration, chemical and structural changes in the brain are as­sumed to interact with genetic propensi­ties to influence gene expression. Once a psychotic event has occurred, it is thought to sensitize the brain so that subsequent events emerge more readily.¹

Schizophrenia—though not the only ill­ness in which psychosis plays a role—is a prototype for psychotic illness, and sev­eral reported sex differences in this dis­order are worth noting.² The incidence of schizophrenia is approximately the same in both sexes, but women show a later age of onset—a paradox in that the brain de­velops at a faster pace in females and theo­retically should reach the threshold for the first appearance of schizophrenia earlier. Women also require lower doses of anti­psychotic medication to recover from an acute psychotic episode and to maintain remission, at least before menopause.^3,4 Both of these differences can be explained as an effect of estrogen on a) gene expres­sion⁵ and b) liver enzymes that metabolize antipsychotics.⁶

The estrogen hypothesis. Women show a tendency toward premenstrual and post­partum exacerbation of symptoms when estrogen levels are relatively low. These clinical observations, confirmed by some but not all studies, have led to the hypoth­esis that estrogens are neuroprotective⁷ and also protect against psychosis.⁸

Estrogen withdrawal in specific brain cells may release a cascade of events that over time can increase the severity of psy­chotic and cognitive symptoms. The reason for suspecting such effects is based on what we know about estrogenic effects on neurotransmitter, cognitive, and stress-induction pathways, and—more fundamentally—on neuronal growth and atrophy.

According to the estrogen hypothesis, women are—to some degree—protected against schizophrenia by their relatively high gonadal estrogen production between puberty and and menopause. Women lose this protection with the onset of perimeno­pausal estrogen fluctuation and decline, accounting for their second peak of illness onset after age 45.

Epidemiologic studies showing a second peak of schizophrenia onset in women (but not men) around the age of menopause sup­port this hypothesis.^9,10 Longitudinal out­comes for schizophrenia—which are better in women than in men during late adolescence or early adulthood11—gradually even out after the first 15 years of illness, suggest­ing that women’s advantage is lost at a time approximating menopause (Box 1).

The question, then, becomes: Is it only because of estrogen loss after age 40 that women become more prone to develop a psychotic illness? Other differences be­tween the sexes that may play roles include immune function, low iron stores, sleep suf­ficiency, thyroid function, exposure to toxic substances (including therapeutic drugs), societal pressures to be slim while aging (Table), and the experience of stress.¹²

CASE CONTINUED
Exhausted and confused
Dr. I is a well-groomed, handsome woman, but she hardly speaks when interviewed, looking frightened and somewhat bewildered. She has never had a mental health problem, nor has anyone in her family. She agrees to stay in the hospital but is not sure why. She has slept no more than 1 or 2 hours in the last several days.

Her early history is unremarkable. She did well in school. After earning a PhD at the Univer­sity of Leipzig, she and her husband immigrated to Canada. Both are university professors. They never decided not to have children, but children hadn’t come. Her menstrual periods stopped 2 years before admission. The question about children is the only 1 that elicits emotion in Dr. I. When I ask about it, tears come to her eyes as she shakes her head.

Her husband reports that she has not been eating well and has, in the last year, started to drink more alcohol than usual—3 to 4 drinks of whiskey a night. She does not smoke cigarettes, and her health generally is good. She uses no medications. Her hus­band describes their marital relationship as very close, although it has become strained in recent weeks because of her unreasonable fears. He admits that their work is always stressful; competition is fierce, with more and more deadlines and less and less leisure time. The couple has few friends and no hobbies.

Late-onset psychosis symptoms
In late-onset psychosis (after age 45), men appear to suffer substantially milder symp­toms and spend less time hospitalized than women.¹³ Women with late-onset schizophrenia have more severe positive symptoms than men and fewer negative symptoms.^14,15 Overall, patients with late-onset schizophrenia have a lower prevalence of looseness of associations and negative symptoms than those with earlier onset.^16,17

In addition, individuals with schizo­phrenia who become ill in middle age have been reported to:
   • show better neuropsychological per­formance (particularly in learning and ab­straction/cognitive flexibility) than those with early onset
   • possibly have larger thalamic volumes
   • respond to lower antipsychotic doses.¹⁸

Auditory and visual hallucinations frequently are observed in patients with comorbid late-onset schizophrenia and auditory and visual impairment.¹⁶ Palmer et al¹⁸ reported no difference in family his­tory of schizophrenia between early and late onset, but this is controversial. Con­vert et al¹⁶ note that most studies reveal a lower lifetime risk of schizophrenia in first-degree relatives of patients with late-onset than early-onset schizophrenia.

CASE CONTINUED
Medical workup
Dr. I’s physical exam is unremarkable. Her thy­roid is not enlarged; there are no breast lumps. On mental status exam, her mood is flat. She is preoccupied with fears of the Nazis. Routine blood tests show slight anemia; fasting glu­cose levels are within normal range.

I give Dr. I zopiclone, 7.5 mg, to help her sleep. The next day she keeps to herself, eats very little, and appears disinterested in her surroundings. Nursing staff report that she often seems frightened. Dr. I asks to use the ward phone to call Germany but is told that she cannot make long distance calls from that phone. This seems to disturb her.

Differential diagnosis
Sensory impairment, substance abuse, and metabolic changes have been implicated in the appearance of psychosis in later life. More specific to women than men, howev­er, are medical and psychiatric precipitants. These include autoimmune disease (and its treatment) and psychiatric disorders, as well as thyroid dysfunction, self-induced starvation (anorexia nervosa) and diet aids, substance use and abuse, insomnia, and iron deficiency (Table).

Autoimmune disease and treatment. Nearly 80% of patients with autoimmune disease are women, and these disorders (as well as their treatment) can manifest as psychosis. Corticosteroids have a well-documented history of triggering psy­chotic symptoms, which are twice as likely in women than in men. The incidence of severe psychosis while taking oral predni­sone ranges from 1.6% to 50% and averages 5.7%. The average daily dose of corticoste­roids for patients who develop psychosis is 59.5 mg/d.

Corticosteroid creams absorbed through skin as well as inhaled and intranasal cor­ticosteroids in their more potent formula­tions can have systemic effects, including psychosis. Nonsteroidal anti-inflammatory drugs such as ibuprofen also can trigger psychosis.¹⁹

Psychiatric disorders. Posttraumatic stress disorder with psychotic symptoms may overlap with categories such as psy­chogenic psychoses, hysterical psychoses, nonaffective remitting psychoses, acute brief psychoses, reactive psychoses, acute and transient psychoses, and bouffées dé­lirantes (in France, the name for transient psychotic reactions).²⁰ Consider these female-predominant conditions in the differential diagnosis, along with micro­psychotic episodes in borderline personal­ity disorder, in which the predominance of women is 3:1.

Medical treatment for depression and anxiety also can lead to psychotic symp­toms through individual susceptibility to the action of specific drugs or through withdrawal effects.

Clinical assessment
Question all women presenting with psy­chosis about eating habits and diet pills, and check for hypokalemia and hypocal­cemia to rule out starvation effects and reactions to stimulants. Also ask about in­halants, and examine for anemia and thy­roid dysfunction. Consider all medications as having the potential to trigger psychotic symptoms.

A family history of illness is important, with a focus on autoimmune disorder and its treatment. A thorough psychiatric history is crucial and needs to include assess­ment of sleep, mood, and relationships with attachment figures. Do not assume ill­nesses of unknown cause (bipolar disorder or schizophrenia) until after a comprehen­sive search for precipitants of psychotic symptoms.

CASE CONTINUED
Guilty feelings
To address her delusions, I start Dr. I on ris­peridone, 2 mg at bedtime. She goes home for the weekend, and her husband reports that she slept throughout the visit. When she returns, she spends a lot of time in bed but is more communicative.

When I ask Dr. I whether she has called Germany, she says she called her recently widowed father. Dr. I begins to cry when talk­ing of her mother, and tells the nurse she feels guilty for not visiting for the last few years. When her mother died 6 months ago, Dr. I had not seen her in 4 years.

Her fears remit with risperidone, main­tained at 2 mg/d, but Dr. I remains depressed and responds slowly to treatment with cital­opram, 20 mg/d, and supportive therapy. Her final diagnosis is mood disorder with psy­chotic features.

Treatment
When treating women with late-onset psy­chosis, remove all potential triggers and address underlying illness. Cognitive ther­apy targeting specific symptoms is useful; antipsychotics probably will be necessary. Age-related physiologic changes make older persons more sensitive to the thera­peutic and toxic effects of antipsychotics.

Estrogen therapy? Women suffering from schizophrenia show significantly lower es­trogen levels than the general population of women, and they experience first-onset or recurrence of a psychotic episode signif­icantly more often in low estrogen phases of the cycle. Estrogens have therefore been postulated to constitute a protective factor against psychosis, which means perimeno­pause is an at-risk period.²¹ Although evi­dence is limited, preliminary studies have found beneficial effects from short-term, off-label use of estrogen therapy in women with psychotic illness (Box 2).

Because continuous use of estrogen plus progestin has been associated with an in­creased risk of adverse effects,²² off-label use of selective estrogen receptor modula­tors (SERMs) also is being investigated in women with schizophrenia. SERMs act as tissue-specific estrogen agonists and an­tagonists because they can either inhibit or enhance estrogen-induced activation of estrogen response element-containing genes.²³

Wong et al²⁴ used a crossover design to compare the SERM raloxifene with place­bo as adjunctive treatment for 6 postmeno­pausal women with schizophrenia. Each woman received 8 weeks of raloxifene, 60 mg/d, and 8 weeks of placebo. Three be­gan with placebo and 3 with raloxifene.

Verbal memory was measured weekly with the California Verbal Learning Test, using 5 memory trials, free and cued short-delay recall, and long-delay recall. At baseline, the participants had lower scores than older adults in the general popula­tion. Eight weeks of placebo improved scores somewhat, suggesting a practice effect. Eight weeks of raloxifene improved cognitive scores to a level similar to that of schizophrenia-free subjects. After 16 weeks, however, cognitive scores in the 2 groups were indistinguishable.

At present I do not recommend estrogen for women with late-onset schizophrenia because the risk is too high and raloxifene does not enter the brain sufficiently to be a valuable cognitive enhancer. Novel SERMs with more specific efficacy for improving cognitive function may prove useful in the future,²⁵ however, as may phytoestro­gens. Adjunctive hormone modulation is a promising area of gender-specific treat­ment for serious mental illness.²⁶

CASE CONCLUSION
Gradually improving
Dr. I’s depression was triggered by her moth­er’s death and regrets about not visiting and not being a mother. The content of her de­lusions was related to her guilt about not having returned to Germany; the delusions were probably triggered by depression, al­cohol intake, her relative hypoestrogenic state, stress at work, lack of social supports, and dependence on her husband.

Over the next few years, Dr. I is maintained on a low dose of risperidone (reduced from 2 mg/d to 1 mg/d) and citalopram (reduced from 20 mg/d to 10 mg/d). She becomes increas­ingly engaged in supportive dynamic therapy, and her symptoms gradually improve.

BOTTOM LINE
Psychosis onset in midlife is mostly a female phenomenon because a perimenopausal estrogen decline increases women’s susceptibility. Seek specific triggers such as medical illness or response to a drug before assuming an illness of unknown cause such as bipolar disorder or schizophrenia. Cognitive therapy targeting specific symptoms is useful; antipsychotics probably will be necessary.

Related Resources
• Women and psychosis: A guide for women and their families. Centre for Addiction and Mental Health. University of Toronto. www.camh.net/About_Addiction_Mental_ Health/Mental_Health_Information/Women_Psychosis.
• Seeman MV. Women and psychosis. www.medscape.com/ viewarticle/408912.
• Chattopadhyay S. Estrogen and schizophrenia: Any link? The Internet Journal of Mental Health. 2004;2(1). www.ispub. com/journal/the_internet_journal_of_mental_health.html.

Drug Brand Names
Citalopram • Celexa                         Prednisone • Deltasone,
Estradiol • Estrace,                                    Orasone, others
   Estrofem, others                           Raloxifene • Evista
Estradiol transdermal •                     Risperidone • Risperdal
   Estraderm , Climara, others
Methylphenidate • Concerta,
   Ritalin, others

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

Discuss this article

Ms. S, age 24, is referred to our team in early December by her primary care physician for “fatigue.” The patient describes going to bed and falling asleep before 9:30 these winter evenings, whereas in summer she went to bed at 11 PM. She craves bread, pasta, and sweets and reports increased appetite in winter compared with summer. Her mood is low, and she misses warm-weather activities of gardening and walking. Fatigue and difficulty concentrating are causing her problems at work and school.

Her history reveals mood elevation in spring as days become longer, with a clear change at approximately March 10 to 20. She reports “spring fever” and feeling “great” last year as soon as daylight saving time began. She slept only 3 hours a night and had a burst of ideas to expand her small business. She threw herself into her work, feeling she was making up for lost time and productivity. She also admits to making a large, misguided business investment during that time.

Upon questioning, she recalls that the previous spring she argued with her father and threw a cup of hot tea at him. When interviewed, Ms. S’s mother describes her daughter at that time as having “a very short fuse,” speaking loud and fast, staying up late at night, and looking as though she was not herself.

Seasonal affective disorder (SAD) is an umbrella term for mood disorders that follow a seasonal pattern of recurrence. Bipolar I disorder (BD I) or bipolar II disorder (BD II) with seasonal pattern (BD SP) is the DSM-IV-TR diagnosis for persons with depressive episodes in the fall or winter and mania (BD I) or hypomania (BD II) in spring or summer ( Table 1 ).¹

This article compares BD SP with major depressive disorder with seasonal pattern (MDD SP), in which depressive episodes usually occur in fall or winter and fully remit in spring or summer.¹ Rather than being categorically distinct from each other, BD SP and MDD SP may represent extreme variants on a seasonal depression continuum from unipolar to bipolar.

Table 1

DSM-IV-TR criteria for seasonal pattern specifier*

Overlap of MDD SP and BD SP

The seasonal pattern specifier can be applied to a diagnosis of MDD, BD I, or BD II.¹ Seasonality-focused assessments, described below, can help characterize seasonal patterns that do not meet full SP criteria but may deserve clinical attention.

Symptom presentation. MDD SP and BD SP share similar atypical depressive symptom presentations and seasonal recurrence patterns ( Box 1 ). Hypersomnia, hyperphagia, and psychomotor retardation are more prevalent in major depressive episodes of bipolar disorders and SAD than in unipolar or nonseasonal mood disorders.^2-4 Individuals with SAD also report fatigue and decreased physical activity,³ both of which are characteristic of bipolar depressive episodes.⁵

Although psychosis and psychiatric hospitalizations are more common in BD I than unipolar disorders,⁶ individuals with BD SP are less likely to report psychosis than those with nonseasonal BD.⁷ Another study found that BD SP patients reported a higher rate of psychiatric hospitalizations than MDD SP patients (28% vs 9.4%).⁶

Recurrence pattern. Major depressive episodes are highly recurrent in both MDD and BD, with or without a seasonal pattern. Approximately 75% of individuals with MDD experience ≥1 recurrence (mean, 10.8 episodes);⁸ MDD SP patients report a mean of 13.4 episodes.⁹ The mean lifetime episodes in BD SP is 20.74, compared with 11.67 in nonseasonal BD.⁷

Cassidy and Carroll¹⁰ measured the frequency of mood episodes in 304 BD patients not assessed for seasonality. Manic episodes peaked in early spring, mixed episodes peaked in late summer or fall, and depressive episodes peaked in fall-winter.

Irregular rhythm. Both BD and MDD SP involve irregularities in daily or circadian rhythms, such as changes in the timing of sleep, melatonin release, and body temperature.^3,5,11 Circadian phase delays—in which internal rhythms lag behind the sleep cycle—are correlated with symptom severity in BD¹² and are implicated in the core pathology of BD¹³ ( Box 2 ). In BD, life events that change social rhythms may disrupt circadian rhythms, triggering mood episodes.⁵

Etiologic hypotheses for both BD and SAD propose that an external event (life stress in BD; decreased photoperiod in SAD) leads to circadian dysregulation and, in turn, mood episodes. Circadian-related hypotheses for SAD and BD are supported by evidence showing efficacy of treatments that manipulate behavioral and circadian rhythms.

Box 1

Box 2

CASE CONTINUED: Seasonal pattern revealed

Ms. S was aware that she is vulnerable to depressive episodes in fall and winter but unaware of a pattern of hypomanic/manic episodes in spring and summer. Her family psychiatric history includes a sister diagnosed with BD I (with no seasonal specifier), and a maternal aunt who has attempted suicide several times.

Ms. S agrees to an assessment plan including a diagnostic interview, interviews measuring symptom severity and pattern of recurrence, routine laboratory examination, and self-report questionnaires. These show that she meets DSM-IV-TR criteria for BD I, depressed, moderate, with seasonal pattern.

Her assessment scores are 28 on the Structured Interview Guide for HDRS-seasonal affective disorder version (SIGH-SAD), 17 on the Hamilton Depression Rating Scale (HDRS), and 11 on the atypical subscale. The HDRS and atypical subscale are components of the SIGH-SAD reflecting typical (eg, insomnia, loss of appetite, etc.) and atypical (eg, hypersomnia, increased appetite, etc.) depression symptoms, respectively. Ms. S’s scores exceed the threshold scores defining a BD SP episode (>20 SIGH-SAD + >10 HDRS + >5 atypical subscale¹⁴ ). Data from self-report questionnaires corroborate this assessment.

We plan to administer the Hypomania Interview Guide (including Hyperthymia) for Seasonal Affective Disorder (HIGH-SAD) during treatment and the following spring to monitor prospectively for hypomanic symptoms.

Assessment tools

After complete assessment for mood episodes and mood disorders based on DSM-IV-TR, an additional assessment for bipolarity and seasonality may be helpful.¹

Screen for bipolarity in patients with SAD to avoid triggering mania or hypomania during treatment. Useful tools include:

• HIGH-SAD¹⁵
• the National Institutes of Health Life Chart Method to establish a recurrent pattern of mood episodes and track treatment efficacy¹⁶
• assessments that characterize sub-threshold bipolar symptoms, such as the Bipolar Spectrum Diagnostic Scale¹⁷ ( see Box 3 ) and the Bipolarity Index.¹⁸

Also obtain collateral reports from significant others, review patient records, and use the same mania and hypomania scales for prospective assessment as the next spring approaches.⁶

Assess seasonality in patients with BD to improve diagnosis and treatment. Characterizing a seasonal pattern may allow you and your patient to predict episodes and treat proactively. Commonly used assessments include the SIGH-SAD and the Structured Clinical Interview for DSM Disorders (SCID) seasonal pattern specifier module.¹⁹

The SIGH-SAD measures symptom severity and provides recovery criteria based on changes in scores during treatment. Response is defined as a 50% reduction in symptoms; remission is >50% improvement in SIGH-SAD + HDRS <7 + atypical <7 or HDRS <2 + atypical <10.¹⁴

CASE CONTINUED: Treatment begins

Considering Ms. S’s diagnosis of BD I SP and the risk of precipitating mania with light treatment, we recommend starting treatment with a mood stabilizer. We narrow our options to those that have a direct antidepressant effect, with the hope that this may reduce the need for future antidepressant medications. For patients diagnosed with BD II SP, we could consider a regimen without mood stabilizers.

We offer Ms. S lithium, a first-line mood stabilizer with evidence of usefulness in treatment before chronotherapeutic interventions and in preventing suicidal behavior. However, Ms. S prefers our second option, lamotrigine, because she is concerned about lithium’s side effects and required blood draws to check drug levels as well as thyroid and kidney status.

Despite causing some initial drowsiness, her lamotrigine dosage is successfully titrated after 2 weeks of treatment to 300 mg/d, without side effects. Only then do we initiate light treatment, which Ms. S wishes to try before antidepressant medications. She also begins sessions with a therapist trained in cognitive-behavioral therapy (CBT) for SAD. (For details of this comprehensive treatment, see Box 4 )

Treating bipolar variant of SAD

Significant differences exist in the clinical management of BD SP and MDD SP, despite their commonalities ( Table 2 ). BD SP treatment remains distinct because of the risk of switching with the use of light therapy or antidepressants and the importance of mood stabilizers, especially in BD I.

Consensus guidelines for treating SAD recommend mood stabilizers and close monitoring during light therapy for patients with BD SP ( Table 3 ).² Therapeutic sleep deprivation can quickly reverse depression during hospitalization but is not used often or recommended for outpatient treatment.²⁰

Light therapy. A small body of evidence suggests that depressive symptoms in BD SP improve with bright light therapy, a treatment with demonstrated efficacy in MDD SP.²¹ No differences in response have been reported between light therapy for winter depressive episodes among individuals with BD SP or MDD SP.^22-24 Light therapy may increase the risk of switching to mania/hypomania in patients with BD SP, however. Clinical supervision is imperative, even for patients thought to have MDD SP, because of the risk of undiagnosed BD.

Regular monitoring by a physician is indicated for individuals taking medications or remedies with photosensitizing effects (such as lithium, thioridazine, or St. John’s wort). An ophthalmologist consultation and monitoring is necessary for patients with preexisting eye problems, those taking photosensitizing medications, and those who develop eye problems during light treatment.^2,6

The recommended starting dose for light therapy in MDD SP is 30 minutes daily in the early morning, but this dose may be too high for individuals with BD SP.²⁵ To minimize the risk of switching, begin light therapy at 5 to 10 minutes daily and slowly increase while monitoring the clinical effect (see Related Resources , for more information about light therapy for affective disorders).

Pharmacotherapy. Pharmacologic treatments have not been studied for effectiveness in BD SP, and we hesitate to provide specific recommendations. Effective treatments may include those used for nonseasonal MDD, nonseasonal BD, and MDD SP. When using any medication for BD SP, weigh the risk of switching states against the potential beneficial effects.²

Year-round mood-stabilizer treatment is indicated to minimize the risk of mood episodes in BD SP, especially in patients with BD I. When treating SAD, mood stabilizers with antidepressant effects—such as lamotrigine or lithium (for maintenance), and quetiapine or aripiprazole (for acute treatment)—are preferable to agents without an antidepressant effect in monotherapy. More-sedating mood stabilizers (such as valproate or carbamazepine) likely would not be as beneficial as less-sedating agents, considering that patients with SAD frequently experience fatigue.

Because of the lack of adequate clinical trials of treatments for BD SP, we suggest that clinicians choose medications and follow algorithms relevant to BD without a seasonal specifier. Use similar schedules and dosages, with individual tailoring.^5,26

Antidepressants that have shown efficacy in MDD SP include fluoxetine, bupropion, citalopram, and sertraline.^6,9,27-29 For patients with BD SP, we initiate antidepressants when:

• light treatment fails
• the patient is unable to travel to the south
• light treatment is not available (often because patients cannot afford the cost, which is not covered by insurance)
• patient lacks time for light treatment.

An additional important consideration is history of response (such as a patient who did not respond well to light therapy in the past but responded very well to a particular antidepressant).

No studies have compared antidepressant classes or individual medications for MDD SP. Clinical wisdom is to base the antidepressant choice, dosages, decision points of when to switch, and schedule of switching (cross-tapering) on individual patients’ symptom clusters and comorbid conditions as well as the medication’s side effects.

Prophylactic treatment with bupropion would seem an appropriate initial choice for a prototypical SAD patient, considering this medication’s more activating effects and FDA approval for SAD treatment.⁹ For the minority of patients with SAD who present with agitation and increased sleepiness, a slightly sedating selective serotonin reuptake inhibitor such as citalopram would make more sense as a first-line treatment. Finally, we would recommend sertraline for patients with marked anxiety—especially panic attacks or obsessive-compulsive symptoms—but without insomnia.

For specific dosages, rely on the literature of treating nonseasonal depression (unipolar or bipolar). It is important to define decision-making points for dosage increases, augmentation, switching to another antidepressant, and cross-tapering, similar to how you would address a nonseasonal depression, typical or atypical.

In our view, treating a patient with BD I SP with an antidepressant alone—without a mood stabilizer—is almost always wrong. For BD II SP we leave it to the clinician to decide, based on individual patients, clinical experience, and ideally in consultation with a peer.

Seasonal dosages. You may wish to seasonally vary medications and dosages for patients with BD SP. Although no strong evidence exists, we recommend 2 options:

• Consider increasing mood-stabilizing medication in spring and summer, with a reduction (but no tapering for BD I) in fall and winter.
• Consider a complete antidepressant taper 2 weeks after daylight saving time begins in spring; taper under increased observation and not faster than 6 weeks, with close attention to emerging symptoms of depression or antidepressant withdrawal.

We do not taper antidepressants before daylight saving time, and we always consider additional stressors, losses, and challenges in our patients’ lives before tapering antidepressants in spring or summer. We also assess and monitor compliance.

Psychotherapy. Referral can be made to clinicians trained in CBT for patients with a seasonal pattern and interpersonal and social rhythm therapy (IPSRT) for BD. Integrative models for SAD and BD propose that psychological and biologic vulnerability factors interact with environmental events (such as winter season or disruption of daily routine) to trigger mood episodes.

CBT adapted for SAD targets mal-adaptive thinking and behavioral disengagement through cognitive therapy and behavioral activation to counteract SAD symptoms.^30,31 Preliminary trials by our group suggest that CBT for MDD SP is an effective acute treatment³⁰ and may prevent future episodes.³²

IPSRT is an adaptation of interpersonal psychotherapy that aims to stabilize social relationships and rhythms in BD.³³ IPSRT posits that irregularity in daily routines leads to circadian dysregulation, precipitating mood episodes in persons vulnerable to BD.³⁴ The degree of regularity in social rhythms achieved in IPSRT is associated with reduced likelihood of recurrence post-treatment.³⁴ If stabilizing social rhythms has a similar effect of regulating circadian rhythms in SAD, IPSRT may be effective in treating BD SP.

Table 2

Physiopathologic findings and clinical management for SAD vs BD

Table 3

Recommended treatment for bipolar disorder with seasonal pattern

CASE CONCLUSION: Ongoing treatment required

After several months of light therapy, Ms. S begins to feel better and reports having more energy. We taper her light therapy to 10 minutes daily in the morning from late February until 1 week after daylight saving time begins in mid-March. Weekly phone calls during this transition screen for signs of hypomania or mania. Lamotrigine is effective in preventing switches in spring.

Future plans include monitoring for hypomania through summer and possibly reinitiating light therapy in fall or winter. Because approximately one-half of individuals who undergo CBT for SAD do not experience another episode the winter after treatment, light therapy will be initiated only if depressive symptoms emerge. A booster session is scheduled with Ms. S’s CBT therapist in early fall to reinforce relapse prevention skills.

Antidepressant therapy will be recommended if full treatment response is not maintained with light therapy and continued use of CBT skills for SAD. During sessions, we emphasize compliance with lamotrigine. On several occasions Ms. S questions the need for ongoing therapy, but with education about the potential effects of mania she agrees to continue treatment as indicated.

Related resources

Seasonality screening tools

• Seasonal Pattern module of the Structured Clinical Interview for DSM Disorders (SCID). www.scid4.org/faq/clinician_version.html.
• Hypomania Interview Guide for Seasonal Affective Disorder (HIGH-SAD). www.chronotherapeutics.org/Tools_ENG.html.
• National Institutes of Health Life Chart Method. www.bipolarnews.org/Clinician%20Life%20Charting.htm.
• Structured Interview Guide for the Hamilton Depression Rating Scale—Seasonal Affective Disorder Version (SIGH-SAD). www.chronotherapeutics.org/Tools_ENG.html.

Bipolarity screening tools

• Bipolar Spectrum Diagnostic Scale. Click here to download.
• Bipolarity Index. http://psycheducation.org/depression/STEPBipolarityIndex.htm.

Light therapy

• Wirz-Justice A, Benedetti F, Terman M. Chronotherapeutics for affective disorders: a clinician’s manual for light and wake therapy. Basel, Switzerland: S. Karger AG; 2009.
• Wirz-Justice A, Benedetti F, Berger M, et al. Chronotherapeutics (light and wake therapy) in affective disorders. Psychol Med. 2005;35(7):939-944.

Psychotherapy

• Rohan KJ. Coping with the seasons: a cognitive-behavioral approach to seasonal affective disorder (therapist guide). New York, NY: Oxford University Press; 2008.
• Frank E. Treating bipolar disorder: a clinician’s guide to interpersonal and social rhythm therapy. New York, NY: Guilford Press, Inc.; 2005.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin XL
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Valproate • Depakote

Disclosures

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

Dr. Postolache received an investigator-initiated award from The LiteBook Company (Vancouver, Canada) via the Society for Light Treatment and Biological Rhythms, as well as research support from Apollo Health (Salt Lake City, UT).

Discuss this article

Ms. S, age 24, is referred to our team in early December by her primary care physician for “fatigue.” The patient describes going to bed and falling asleep before 9:30 these winter evenings, whereas in summer she went to bed at 11 PM. She craves bread, pasta, and sweets and reports increased appetite in winter compared with summer. Her mood is low, and she misses warm-weather activities of gardening and walking. Fatigue and difficulty concentrating are causing her problems at work and school.

Her history reveals mood elevation in spring as days become longer, with a clear change at approximately March 10 to 20. She reports “spring fever” and feeling “great” last year as soon as daylight saving time began. She slept only 3 hours a night and had a burst of ideas to expand her small business. She threw herself into her work, feeling she was making up for lost time and productivity. She also admits to making a large, misguided business investment during that time.

Upon questioning, she recalls that the previous spring she argued with her father and threw a cup of hot tea at him. When interviewed, Ms. S’s mother describes her daughter at that time as having “a very short fuse,” speaking loud and fast, staying up late at night, and looking as though she was not herself.

Seasonal affective disorder (SAD) is an umbrella term for mood disorders that follow a seasonal pattern of recurrence. Bipolar I disorder (BD I) or bipolar II disorder (BD II) with seasonal pattern (BD SP) is the DSM-IV-TR diagnosis for persons with depressive episodes in the fall or winter and mania (BD I) or hypomania (BD II) in spring or summer ( Table 1 ).¹

This article compares BD SP with major depressive disorder with seasonal pattern (MDD SP), in which depressive episodes usually occur in fall or winter and fully remit in spring or summer.¹ Rather than being categorically distinct from each other, BD SP and MDD SP may represent extreme variants on a seasonal depression continuum from unipolar to bipolar.

Table 1

DSM-IV-TR criteria for seasonal pattern specifier*

Overlap of MDD SP and BD SP

The seasonal pattern specifier can be applied to a diagnosis of MDD, BD I, or BD II.¹ Seasonality-focused assessments, described below, can help characterize seasonal patterns that do not meet full SP criteria but may deserve clinical attention.

Symptom presentation. MDD SP and BD SP share similar atypical depressive symptom presentations and seasonal recurrence patterns ( Box 1 ). Hypersomnia, hyperphagia, and psychomotor retardation are more prevalent in major depressive episodes of bipolar disorders and SAD than in unipolar or nonseasonal mood disorders.^2-4 Individuals with SAD also report fatigue and decreased physical activity,³ both of which are characteristic of bipolar depressive episodes.⁵

Although psychosis and psychiatric hospitalizations are more common in BD I than unipolar disorders,⁶ individuals with BD SP are less likely to report psychosis than those with nonseasonal BD.⁷ Another study found that BD SP patients reported a higher rate of psychiatric hospitalizations than MDD SP patients (28% vs 9.4%).⁶

Recurrence pattern. Major depressive episodes are highly recurrent in both MDD and BD, with or without a seasonal pattern. Approximately 75% of individuals with MDD experience ≥1 recurrence (mean, 10.8 episodes);⁸ MDD SP patients report a mean of 13.4 episodes.⁹ The mean lifetime episodes in BD SP is 20.74, compared with 11.67 in nonseasonal BD.⁷

Cassidy and Carroll¹⁰ measured the frequency of mood episodes in 304 BD patients not assessed for seasonality. Manic episodes peaked in early spring, mixed episodes peaked in late summer or fall, and depressive episodes peaked in fall-winter.

Irregular rhythm. Both BD and MDD SP involve irregularities in daily or circadian rhythms, such as changes in the timing of sleep, melatonin release, and body temperature.^3,5,11 Circadian phase delays—in which internal rhythms lag behind the sleep cycle—are correlated with symptom severity in BD¹² and are implicated in the core pathology of BD¹³ ( Box 2 ). In BD, life events that change social rhythms may disrupt circadian rhythms, triggering mood episodes.⁵

Etiologic hypotheses for both BD and SAD propose that an external event (life stress in BD; decreased photoperiod in SAD) leads to circadian dysregulation and, in turn, mood episodes. Circadian-related hypotheses for SAD and BD are supported by evidence showing efficacy of treatments that manipulate behavioral and circadian rhythms.

Box 1

Box 2

CASE CONTINUED: Seasonal pattern revealed

Ms. S was aware that she is vulnerable to depressive episodes in fall and winter but unaware of a pattern of hypomanic/manic episodes in spring and summer. Her family psychiatric history includes a sister diagnosed with BD I (with no seasonal specifier), and a maternal aunt who has attempted suicide several times.

Ms. S agrees to an assessment plan including a diagnostic interview, interviews measuring symptom severity and pattern of recurrence, routine laboratory examination, and self-report questionnaires. These show that she meets DSM-IV-TR criteria for BD I, depressed, moderate, with seasonal pattern.

Her assessment scores are 28 on the Structured Interview Guide for HDRS-seasonal affective disorder version (SIGH-SAD), 17 on the Hamilton Depression Rating Scale (HDRS), and 11 on the atypical subscale. The HDRS and atypical subscale are components of the SIGH-SAD reflecting typical (eg, insomnia, loss of appetite, etc.) and atypical (eg, hypersomnia, increased appetite, etc.) depression symptoms, respectively. Ms. S’s scores exceed the threshold scores defining a BD SP episode (>20 SIGH-SAD + >10 HDRS + >5 atypical subscale¹⁴ ). Data from self-report questionnaires corroborate this assessment.

We plan to administer the Hypomania Interview Guide (including Hyperthymia) for Seasonal Affective Disorder (HIGH-SAD) during treatment and the following spring to monitor prospectively for hypomanic symptoms.

Assessment tools

After complete assessment for mood episodes and mood disorders based on DSM-IV-TR, an additional assessment for bipolarity and seasonality may be helpful.¹

Screen for bipolarity in patients with SAD to avoid triggering mania or hypomania during treatment. Useful tools include:

• HIGH-SAD¹⁵
• the National Institutes of Health Life Chart Method to establish a recurrent pattern of mood episodes and track treatment efficacy¹⁶
• assessments that characterize sub-threshold bipolar symptoms, such as the Bipolar Spectrum Diagnostic Scale¹⁷ ( see Box 3 ) and the Bipolarity Index.¹⁸

Also obtain collateral reports from significant others, review patient records, and use the same mania and hypomania scales for prospective assessment as the next spring approaches.⁶

Assess seasonality in patients with BD to improve diagnosis and treatment. Characterizing a seasonal pattern may allow you and your patient to predict episodes and treat proactively. Commonly used assessments include the SIGH-SAD and the Structured Clinical Interview for DSM Disorders (SCID) seasonal pattern specifier module.¹⁹

The SIGH-SAD measures symptom severity and provides recovery criteria based on changes in scores during treatment. Response is defined as a 50% reduction in symptoms; remission is >50% improvement in SIGH-SAD + HDRS <7 + atypical <7 or HDRS <2 + atypical <10.¹⁴

CASE CONTINUED: Treatment begins

Considering Ms. S’s diagnosis of BD I SP and the risk of precipitating mania with light treatment, we recommend starting treatment with a mood stabilizer. We narrow our options to those that have a direct antidepressant effect, with the hope that this may reduce the need for future antidepressant medications. For patients diagnosed with BD II SP, we could consider a regimen without mood stabilizers.

We offer Ms. S lithium, a first-line mood stabilizer with evidence of usefulness in treatment before chronotherapeutic interventions and in preventing suicidal behavior. However, Ms. S prefers our second option, lamotrigine, because she is concerned about lithium’s side effects and required blood draws to check drug levels as well as thyroid and kidney status.

Despite causing some initial drowsiness, her lamotrigine dosage is successfully titrated after 2 weeks of treatment to 300 mg/d, without side effects. Only then do we initiate light treatment, which Ms. S wishes to try before antidepressant medications. She also begins sessions with a therapist trained in cognitive-behavioral therapy (CBT) for SAD. (For details of this comprehensive treatment, see Box 4 )

Treating bipolar variant of SAD

Significant differences exist in the clinical management of BD SP and MDD SP, despite their commonalities ( Table 2 ). BD SP treatment remains distinct because of the risk of switching with the use of light therapy or antidepressants and the importance of mood stabilizers, especially in BD I.

Consensus guidelines for treating SAD recommend mood stabilizers and close monitoring during light therapy for patients with BD SP ( Table 3 ).² Therapeutic sleep deprivation can quickly reverse depression during hospitalization but is not used often or recommended for outpatient treatment.²⁰

Light therapy. A small body of evidence suggests that depressive symptoms in BD SP improve with bright light therapy, a treatment with demonstrated efficacy in MDD SP.²¹ No differences in response have been reported between light therapy for winter depressive episodes among individuals with BD SP or MDD SP.^22-24 Light therapy may increase the risk of switching to mania/hypomania in patients with BD SP, however. Clinical supervision is imperative, even for patients thought to have MDD SP, because of the risk of undiagnosed BD.

Regular monitoring by a physician is indicated for individuals taking medications or remedies with photosensitizing effects (such as lithium, thioridazine, or St. John’s wort). An ophthalmologist consultation and monitoring is necessary for patients with preexisting eye problems, those taking photosensitizing medications, and those who develop eye problems during light treatment.^2,6

The recommended starting dose for light therapy in MDD SP is 30 minutes daily in the early morning, but this dose may be too high for individuals with BD SP.²⁵ To minimize the risk of switching, begin light therapy at 5 to 10 minutes daily and slowly increase while monitoring the clinical effect (see Related Resources , for more information about light therapy for affective disorders).

Pharmacotherapy. Pharmacologic treatments have not been studied for effectiveness in BD SP, and we hesitate to provide specific recommendations. Effective treatments may include those used for nonseasonal MDD, nonseasonal BD, and MDD SP. When using any medication for BD SP, weigh the risk of switching states against the potential beneficial effects.²

Year-round mood-stabilizer treatment is indicated to minimize the risk of mood episodes in BD SP, especially in patients with BD I. When treating SAD, mood stabilizers with antidepressant effects—such as lamotrigine or lithium (for maintenance), and quetiapine or aripiprazole (for acute treatment)—are preferable to agents without an antidepressant effect in monotherapy. More-sedating mood stabilizers (such as valproate or carbamazepine) likely would not be as beneficial as less-sedating agents, considering that patients with SAD frequently experience fatigue.

Because of the lack of adequate clinical trials of treatments for BD SP, we suggest that clinicians choose medications and follow algorithms relevant to BD without a seasonal specifier. Use similar schedules and dosages, with individual tailoring.^5,26

Antidepressants that have shown efficacy in MDD SP include fluoxetine, bupropion, citalopram, and sertraline.^6,9,27-29 For patients with BD SP, we initiate antidepressants when:

• light treatment fails
• the patient is unable to travel to the south
• light treatment is not available (often because patients cannot afford the cost, which is not covered by insurance)
• patient lacks time for light treatment.

An additional important consideration is history of response (such as a patient who did not respond well to light therapy in the past but responded very well to a particular antidepressant).

No studies have compared antidepressant classes or individual medications for MDD SP. Clinical wisdom is to base the antidepressant choice, dosages, decision points of when to switch, and schedule of switching (cross-tapering) on individual patients’ symptom clusters and comorbid conditions as well as the medication’s side effects.

Prophylactic treatment with bupropion would seem an appropriate initial choice for a prototypical SAD patient, considering this medication’s more activating effects and FDA approval for SAD treatment.⁹ For the minority of patients with SAD who present with agitation and increased sleepiness, a slightly sedating selective serotonin reuptake inhibitor such as citalopram would make more sense as a first-line treatment. Finally, we would recommend sertraline for patients with marked anxiety—especially panic attacks or obsessive-compulsive symptoms—but without insomnia.

For specific dosages, rely on the literature of treating nonseasonal depression (unipolar or bipolar). It is important to define decision-making points for dosage increases, augmentation, switching to another antidepressant, and cross-tapering, similar to how you would address a nonseasonal depression, typical or atypical.

In our view, treating a patient with BD I SP with an antidepressant alone—without a mood stabilizer—is almost always wrong. For BD II SP we leave it to the clinician to decide, based on individual patients, clinical experience, and ideally in consultation with a peer.

Seasonal dosages. You may wish to seasonally vary medications and dosages for patients with BD SP. Although no strong evidence exists, we recommend 2 options:

• Consider increasing mood-stabilizing medication in spring and summer, with a reduction (but no tapering for BD I) in fall and winter.
• Consider a complete antidepressant taper 2 weeks after daylight saving time begins in spring; taper under increased observation and not faster than 6 weeks, with close attention to emerging symptoms of depression or antidepressant withdrawal.

We do not taper antidepressants before daylight saving time, and we always consider additional stressors, losses, and challenges in our patients’ lives before tapering antidepressants in spring or summer. We also assess and monitor compliance.

Psychotherapy. Referral can be made to clinicians trained in CBT for patients with a seasonal pattern and interpersonal and social rhythm therapy (IPSRT) for BD. Integrative models for SAD and BD propose that psychological and biologic vulnerability factors interact with environmental events (such as winter season or disruption of daily routine) to trigger mood episodes.

CBT adapted for SAD targets mal-adaptive thinking and behavioral disengagement through cognitive therapy and behavioral activation to counteract SAD symptoms.^30,31 Preliminary trials by our group suggest that CBT for MDD SP is an effective acute treatment³⁰ and may prevent future episodes.³²

IPSRT is an adaptation of interpersonal psychotherapy that aims to stabilize social relationships and rhythms in BD.³³ IPSRT posits that irregularity in daily routines leads to circadian dysregulation, precipitating mood episodes in persons vulnerable to BD.³⁴ The degree of regularity in social rhythms achieved in IPSRT is associated with reduced likelihood of recurrence post-treatment.³⁴ If stabilizing social rhythms has a similar effect of regulating circadian rhythms in SAD, IPSRT may be effective in treating BD SP.

Table 2

Physiopathologic findings and clinical management for SAD vs BD

Table 3

Recommended treatment for bipolar disorder with seasonal pattern

CASE CONCLUSION: Ongoing treatment required

After several months of light therapy, Ms. S begins to feel better and reports having more energy. We taper her light therapy to 10 minutes daily in the morning from late February until 1 week after daylight saving time begins in mid-March. Weekly phone calls during this transition screen for signs of hypomania or mania. Lamotrigine is effective in preventing switches in spring.

Future plans include monitoring for hypomania through summer and possibly reinitiating light therapy in fall or winter. Because approximately one-half of individuals who undergo CBT for SAD do not experience another episode the winter after treatment, light therapy will be initiated only if depressive symptoms emerge. A booster session is scheduled with Ms. S’s CBT therapist in early fall to reinforce relapse prevention skills.

Antidepressant therapy will be recommended if full treatment response is not maintained with light therapy and continued use of CBT skills for SAD. During sessions, we emphasize compliance with lamotrigine. On several occasions Ms. S questions the need for ongoing therapy, but with education about the potential effects of mania she agrees to continue treatment as indicated.

Related resources

Seasonality screening tools

• Seasonal Pattern module of the Structured Clinical Interview for DSM Disorders (SCID). www.scid4.org/faq/clinician_version.html.
• Hypomania Interview Guide for Seasonal Affective Disorder (HIGH-SAD). www.chronotherapeutics.org/Tools_ENG.html.
• National Institutes of Health Life Chart Method. www.bipolarnews.org/Clinician%20Life%20Charting.htm.
• Structured Interview Guide for the Hamilton Depression Rating Scale—Seasonal Affective Disorder Version (SIGH-SAD). www.chronotherapeutics.org/Tools_ENG.html.

Bipolarity screening tools

• Bipolar Spectrum Diagnostic Scale. Click here to download.
• Bipolarity Index. http://psycheducation.org/depression/STEPBipolarityIndex.htm.

Light therapy

• Wirz-Justice A, Benedetti F, Terman M. Chronotherapeutics for affective disorders: a clinician’s manual for light and wake therapy. Basel, Switzerland: S. Karger AG; 2009.
• Wirz-Justice A, Benedetti F, Berger M, et al. Chronotherapeutics (light and wake therapy) in affective disorders. Psychol Med. 2005;35(7):939-944.

Psychotherapy

• Rohan KJ. Coping with the seasons: a cognitive-behavioral approach to seasonal affective disorder (therapist guide). New York, NY: Oxford University Press; 2008.
• Frank E. Treating bipolar disorder: a clinician’s guide to interpersonal and social rhythm therapy. New York, NY: Guilford Press, Inc.; 2005.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin XL
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Valproate • Depakote

Disclosures

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

Dr. Postolache received an investigator-initiated award from The LiteBook Company (Vancouver, Canada) via the Society for Light Treatment and Biological Rhythms, as well as research support from Apollo Health (Salt Lake City, UT).

Discuss this article

Ms. S, age 24, is referred to our team in early December by her primary care physician for “fatigue.” The patient describes going to bed and falling asleep before 9:30 these winter evenings, whereas in summer she went to bed at 11 PM. She craves bread, pasta, and sweets and reports increased appetite in winter compared with summer. Her mood is low, and she misses warm-weather activities of gardening and walking. Fatigue and difficulty concentrating are causing her problems at work and school.

Her history reveals mood elevation in spring as days become longer, with a clear change at approximately March 10 to 20. She reports “spring fever” and feeling “great” last year as soon as daylight saving time began. She slept only 3 hours a night and had a burst of ideas to expand her small business. She threw herself into her work, feeling she was making up for lost time and productivity. She also admits to making a large, misguided business investment during that time.

Upon questioning, she recalls that the previous spring she argued with her father and threw a cup of hot tea at him. When interviewed, Ms. S’s mother describes her daughter at that time as having “a very short fuse,” speaking loud and fast, staying up late at night, and looking as though she was not herself.

Seasonal affective disorder (SAD) is an umbrella term for mood disorders that follow a seasonal pattern of recurrence. Bipolar I disorder (BD I) or bipolar II disorder (BD II) with seasonal pattern (BD SP) is the DSM-IV-TR diagnosis for persons with depressive episodes in the fall or winter and mania (BD I) or hypomania (BD II) in spring or summer ( Table 1 ).¹

This article compares BD SP with major depressive disorder with seasonal pattern (MDD SP), in which depressive episodes usually occur in fall or winter and fully remit in spring or summer.¹ Rather than being categorically distinct from each other, BD SP and MDD SP may represent extreme variants on a seasonal depression continuum from unipolar to bipolar.

Table 1

DSM-IV-TR criteria for seasonal pattern specifier*

Overlap of MDD SP and BD SP

The seasonal pattern specifier can be applied to a diagnosis of MDD, BD I, or BD II.¹ Seasonality-focused assessments, described below, can help characterize seasonal patterns that do not meet full SP criteria but may deserve clinical attention.

Symptom presentation. MDD SP and BD SP share similar atypical depressive symptom presentations and seasonal recurrence patterns ( Box 1 ). Hypersomnia, hyperphagia, and psychomotor retardation are more prevalent in major depressive episodes of bipolar disorders and SAD than in unipolar or nonseasonal mood disorders.^2-4 Individuals with SAD also report fatigue and decreased physical activity,³ both of which are characteristic of bipolar depressive episodes.⁵

Although psychosis and psychiatric hospitalizations are more common in BD I than unipolar disorders,⁶ individuals with BD SP are less likely to report psychosis than those with nonseasonal BD.⁷ Another study found that BD SP patients reported a higher rate of psychiatric hospitalizations than MDD SP patients (28% vs 9.4%).⁶

Recurrence pattern. Major depressive episodes are highly recurrent in both MDD and BD, with or without a seasonal pattern. Approximately 75% of individuals with MDD experience ≥1 recurrence (mean, 10.8 episodes);⁸ MDD SP patients report a mean of 13.4 episodes.⁹ The mean lifetime episodes in BD SP is 20.74, compared with 11.67 in nonseasonal BD.⁷

Cassidy and Carroll¹⁰ measured the frequency of mood episodes in 304 BD patients not assessed for seasonality. Manic episodes peaked in early spring, mixed episodes peaked in late summer or fall, and depressive episodes peaked in fall-winter.

Irregular rhythm. Both BD and MDD SP involve irregularities in daily or circadian rhythms, such as changes in the timing of sleep, melatonin release, and body temperature.^3,5,11 Circadian phase delays—in which internal rhythms lag behind the sleep cycle—are correlated with symptom severity in BD¹² and are implicated in the core pathology of BD¹³ ( Box 2 ). In BD, life events that change social rhythms may disrupt circadian rhythms, triggering mood episodes.⁵

Etiologic hypotheses for both BD and SAD propose that an external event (life stress in BD; decreased photoperiod in SAD) leads to circadian dysregulation and, in turn, mood episodes. Circadian-related hypotheses for SAD and BD are supported by evidence showing efficacy of treatments that manipulate behavioral and circadian rhythms.

Box 1

Box 2

CASE CONTINUED: Seasonal pattern revealed

Ms. S was aware that she is vulnerable to depressive episodes in fall and winter but unaware of a pattern of hypomanic/manic episodes in spring and summer. Her family psychiatric history includes a sister diagnosed with BD I (with no seasonal specifier), and a maternal aunt who has attempted suicide several times.

Ms. S agrees to an assessment plan including a diagnostic interview, interviews measuring symptom severity and pattern of recurrence, routine laboratory examination, and self-report questionnaires. These show that she meets DSM-IV-TR criteria for BD I, depressed, moderate, with seasonal pattern.

Her assessment scores are 28 on the Structured Interview Guide for HDRS-seasonal affective disorder version (SIGH-SAD), 17 on the Hamilton Depression Rating Scale (HDRS), and 11 on the atypical subscale. The HDRS and atypical subscale are components of the SIGH-SAD reflecting typical (eg, insomnia, loss of appetite, etc.) and atypical (eg, hypersomnia, increased appetite, etc.) depression symptoms, respectively. Ms. S’s scores exceed the threshold scores defining a BD SP episode (>20 SIGH-SAD + >10 HDRS + >5 atypical subscale¹⁴ ). Data from self-report questionnaires corroborate this assessment.

We plan to administer the Hypomania Interview Guide (including Hyperthymia) for Seasonal Affective Disorder (HIGH-SAD) during treatment and the following spring to monitor prospectively for hypomanic symptoms.

Assessment tools

After complete assessment for mood episodes and mood disorders based on DSM-IV-TR, an additional assessment for bipolarity and seasonality may be helpful.¹

Screen for bipolarity in patients with SAD to avoid triggering mania or hypomania during treatment. Useful tools include:

• HIGH-SAD¹⁵
• the National Institutes of Health Life Chart Method to establish a recurrent pattern of mood episodes and track treatment efficacy¹⁶
• assessments that characterize sub-threshold bipolar symptoms, such as the Bipolar Spectrum Diagnostic Scale¹⁷ ( see Box 3 ) and the Bipolarity Index.¹⁸

Also obtain collateral reports from significant others, review patient records, and use the same mania and hypomania scales for prospective assessment as the next spring approaches.⁶

Assess seasonality in patients with BD to improve diagnosis and treatment. Characterizing a seasonal pattern may allow you and your patient to predict episodes and treat proactively. Commonly used assessments include the SIGH-SAD and the Structured Clinical Interview for DSM Disorders (SCID) seasonal pattern specifier module.¹⁹

The SIGH-SAD measures symptom severity and provides recovery criteria based on changes in scores during treatment. Response is defined as a 50% reduction in symptoms; remission is >50% improvement in SIGH-SAD + HDRS <7 + atypical <7 or HDRS <2 + atypical <10.¹⁴

CASE CONTINUED: Treatment begins

Considering Ms. S’s diagnosis of BD I SP and the risk of precipitating mania with light treatment, we recommend starting treatment with a mood stabilizer. We narrow our options to those that have a direct antidepressant effect, with the hope that this may reduce the need for future antidepressant medications. For patients diagnosed with BD II SP, we could consider a regimen without mood stabilizers.

We offer Ms. S lithium, a first-line mood stabilizer with evidence of usefulness in treatment before chronotherapeutic interventions and in preventing suicidal behavior. However, Ms. S prefers our second option, lamotrigine, because she is concerned about lithium’s side effects and required blood draws to check drug levels as well as thyroid and kidney status.

Despite causing some initial drowsiness, her lamotrigine dosage is successfully titrated after 2 weeks of treatment to 300 mg/d, without side effects. Only then do we initiate light treatment, which Ms. S wishes to try before antidepressant medications. She also begins sessions with a therapist trained in cognitive-behavioral therapy (CBT) for SAD. (For details of this comprehensive treatment, see Box 4 )

Treating bipolar variant of SAD

Significant differences exist in the clinical management of BD SP and MDD SP, despite their commonalities ( Table 2 ). BD SP treatment remains distinct because of the risk of switching with the use of light therapy or antidepressants and the importance of mood stabilizers, especially in BD I.

Consensus guidelines for treating SAD recommend mood stabilizers and close monitoring during light therapy for patients with BD SP ( Table 3 ).² Therapeutic sleep deprivation can quickly reverse depression during hospitalization but is not used often or recommended for outpatient treatment.²⁰

Light therapy. A small body of evidence suggests that depressive symptoms in BD SP improve with bright light therapy, a treatment with demonstrated efficacy in MDD SP.²¹ No differences in response have been reported between light therapy for winter depressive episodes among individuals with BD SP or MDD SP.^22-24 Light therapy may increase the risk of switching to mania/hypomania in patients with BD SP, however. Clinical supervision is imperative, even for patients thought to have MDD SP, because of the risk of undiagnosed BD.

Regular monitoring by a physician is indicated for individuals taking medications or remedies with photosensitizing effects (such as lithium, thioridazine, or St. John’s wort). An ophthalmologist consultation and monitoring is necessary for patients with preexisting eye problems, those taking photosensitizing medications, and those who develop eye problems during light treatment.^2,6

The recommended starting dose for light therapy in MDD SP is 30 minutes daily in the early morning, but this dose may be too high for individuals with BD SP.²⁵ To minimize the risk of switching, begin light therapy at 5 to 10 minutes daily and slowly increase while monitoring the clinical effect (see Related Resources , for more information about light therapy for affective disorders).

Pharmacotherapy. Pharmacologic treatments have not been studied for effectiveness in BD SP, and we hesitate to provide specific recommendations. Effective treatments may include those used for nonseasonal MDD, nonseasonal BD, and MDD SP. When using any medication for BD SP, weigh the risk of switching states against the potential beneficial effects.²

Year-round mood-stabilizer treatment is indicated to minimize the risk of mood episodes in BD SP, especially in patients with BD I. When treating SAD, mood stabilizers with antidepressant effects—such as lamotrigine or lithium (for maintenance), and quetiapine or aripiprazole (for acute treatment)—are preferable to agents without an antidepressant effect in monotherapy. More-sedating mood stabilizers (such as valproate or carbamazepine) likely would not be as beneficial as less-sedating agents, considering that patients with SAD frequently experience fatigue.

Because of the lack of adequate clinical trials of treatments for BD SP, we suggest that clinicians choose medications and follow algorithms relevant to BD without a seasonal specifier. Use similar schedules and dosages, with individual tailoring.^5,26

Antidepressants that have shown efficacy in MDD SP include fluoxetine, bupropion, citalopram, and sertraline.^6,9,27-29 For patients with BD SP, we initiate antidepressants when:

• light treatment fails
• the patient is unable to travel to the south
• light treatment is not available (often because patients cannot afford the cost, which is not covered by insurance)
• patient lacks time for light treatment.

An additional important consideration is history of response (such as a patient who did not respond well to light therapy in the past but responded very well to a particular antidepressant).

No studies have compared antidepressant classes or individual medications for MDD SP. Clinical wisdom is to base the antidepressant choice, dosages, decision points of when to switch, and schedule of switching (cross-tapering) on individual patients’ symptom clusters and comorbid conditions as well as the medication’s side effects.

Prophylactic treatment with bupropion would seem an appropriate initial choice for a prototypical SAD patient, considering this medication’s more activating effects and FDA approval for SAD treatment.⁹ For the minority of patients with SAD who present with agitation and increased sleepiness, a slightly sedating selective serotonin reuptake inhibitor such as citalopram would make more sense as a first-line treatment. Finally, we would recommend sertraline for patients with marked anxiety—especially panic attacks or obsessive-compulsive symptoms—but without insomnia.

For specific dosages, rely on the literature of treating nonseasonal depression (unipolar or bipolar). It is important to define decision-making points for dosage increases, augmentation, switching to another antidepressant, and cross-tapering, similar to how you would address a nonseasonal depression, typical or atypical.

In our view, treating a patient with BD I SP with an antidepressant alone—without a mood stabilizer—is almost always wrong. For BD II SP we leave it to the clinician to decide, based on individual patients, clinical experience, and ideally in consultation with a peer.

Seasonal dosages. You may wish to seasonally vary medications and dosages for patients with BD SP. Although no strong evidence exists, we recommend 2 options:

• Consider increasing mood-stabilizing medication in spring and summer, with a reduction (but no tapering for BD I) in fall and winter.
• Consider a complete antidepressant taper 2 weeks after daylight saving time begins in spring; taper under increased observation and not faster than 6 weeks, with close attention to emerging symptoms of depression or antidepressant withdrawal.

We do not taper antidepressants before daylight saving time, and we always consider additional stressors, losses, and challenges in our patients’ lives before tapering antidepressants in spring or summer. We also assess and monitor compliance.

Psychotherapy. Referral can be made to clinicians trained in CBT for patients with a seasonal pattern and interpersonal and social rhythm therapy (IPSRT) for BD. Integrative models for SAD and BD propose that psychological and biologic vulnerability factors interact with environmental events (such as winter season or disruption of daily routine) to trigger mood episodes.

CBT adapted for SAD targets mal-adaptive thinking and behavioral disengagement through cognitive therapy and behavioral activation to counteract SAD symptoms.^30,31 Preliminary trials by our group suggest that CBT for MDD SP is an effective acute treatment³⁰ and may prevent future episodes.³²

IPSRT is an adaptation of interpersonal psychotherapy that aims to stabilize social relationships and rhythms in BD.³³ IPSRT posits that irregularity in daily routines leads to circadian dysregulation, precipitating mood episodes in persons vulnerable to BD.³⁴ The degree of regularity in social rhythms achieved in IPSRT is associated with reduced likelihood of recurrence post-treatment.³⁴ If stabilizing social rhythms has a similar effect of regulating circadian rhythms in SAD, IPSRT may be effective in treating BD SP.

Table 2

Physiopathologic findings and clinical management for SAD vs BD

Table 3

Recommended treatment for bipolar disorder with seasonal pattern

CASE CONCLUSION: Ongoing treatment required

After several months of light therapy, Ms. S begins to feel better and reports having more energy. We taper her light therapy to 10 minutes daily in the morning from late February until 1 week after daylight saving time begins in mid-March. Weekly phone calls during this transition screen for signs of hypomania or mania. Lamotrigine is effective in preventing switches in spring.

Future plans include monitoring for hypomania through summer and possibly reinitiating light therapy in fall or winter. Because approximately one-half of individuals who undergo CBT for SAD do not experience another episode the winter after treatment, light therapy will be initiated only if depressive symptoms emerge. A booster session is scheduled with Ms. S’s CBT therapist in early fall to reinforce relapse prevention skills.

Antidepressant therapy will be recommended if full treatment response is not maintained with light therapy and continued use of CBT skills for SAD. During sessions, we emphasize compliance with lamotrigine. On several occasions Ms. S questions the need for ongoing therapy, but with education about the potential effects of mania she agrees to continue treatment as indicated.

Related resources

Seasonality screening tools

• Seasonal Pattern module of the Structured Clinical Interview for DSM Disorders (SCID). www.scid4.org/faq/clinician_version.html.
• Hypomania Interview Guide for Seasonal Affective Disorder (HIGH-SAD). www.chronotherapeutics.org/Tools_ENG.html.
• National Institutes of Health Life Chart Method. www.bipolarnews.org/Clinician%20Life%20Charting.htm.
• Structured Interview Guide for the Hamilton Depression Rating Scale—Seasonal Affective Disorder Version (SIGH-SAD). www.chronotherapeutics.org/Tools_ENG.html.

Bipolarity screening tools

• Bipolar Spectrum Diagnostic Scale. Click here to download.
• Bipolarity Index. http://psycheducation.org/depression/STEPBipolarityIndex.htm.

Light therapy

• Wirz-Justice A, Benedetti F, Terman M. Chronotherapeutics for affective disorders: a clinician’s manual for light and wake therapy. Basel, Switzerland: S. Karger AG; 2009.
• Wirz-Justice A, Benedetti F, Berger M, et al. Chronotherapeutics (light and wake therapy) in affective disorders. Psychol Med. 2005;35(7):939-944.

Psychotherapy

• Rohan KJ. Coping with the seasons: a cognitive-behavioral approach to seasonal affective disorder (therapist guide). New York, NY: Oxford University Press; 2008.
• Frank E. Treating bipolar disorder: a clinician’s guide to interpersonal and social rhythm therapy. New York, NY: Guilford Press, Inc.; 2005.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin XL
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Valproate • Depakote

Disclosures

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

Dr. Postolache received an investigator-initiated award from The LiteBook Company (Vancouver, Canada) via the Society for Light Treatment and Biological Rhythms, as well as research support from Apollo Health (Salt Lake City, UT).

Discuss this article

As the eldest post-World War II “baby boomers” turn 64 this year, relaxed social attitudes about substance use during their lifetimes may predict an increasing risk for substance use disorders (SUDs) in older Americans.¹ This presents challenges for psychiatric clinicians:

• Common screening tools used for younger patients might not adequately diagnose SUDs in patients clinically defined as elderly (age ≥65).
• DSM-IV-TR’s definition of substance use as causing clinically significant impairment or distress—such as occupational difficulties, legal problems, or decreased participation in social activities—might not apply to older patients, or these problems could be caused by other factors in older individuals.²

This article describes screening and treatment approaches shown to be most effective for identifying and managing primary SUDs in older patients. Our goal is to help you ask the right questions and provide appropriate care.

Phase-of-life issues

Most older adults have a primary care physician, but their SUDs often go unrecognized.³ Clinicians and family members might hesitate to ask about substance use or prescription medication misuse, and complications—such as falls or cognitive impairment—may be misattributed to normal aging. Thus, SUD screening of older individuals referred for psychiatric care is important.

Older adults respond with higher adherence rates when SUD treatment addresses age-specific issues—such as recent losses, medical problems, and challenges of keeping scheduled appointments or multiple providers/referrals. A combination of psychosocial and biologic treatments may be most beneficial. Although outcomes vary, some evidence indicates that age-specific programs for older alcoholics significantly improve abstinence rates at 6 and 12 months, compared with mixed-age programs⁴ ( see Related Resources ).

We recommend that you incorporate phase-of-life considerations at all stages of treatment. These include:

• education regarding lowered alcohol intake recommendations
• assessment tools that use criteria relevant to older adults
• treatment interventions that involve age-specific groups and programming.

Screening tools

In a routine office visit, a sensible approach is to screen for alcohol, tobacco, and prescription medication misuse. First-line screening tools for alcohol abuse include the AUDIT-5, CAGE, or MAST-G ( Table 1 ), accompanied by questions about medication side effects and observation of behavioral signs of medication misuse.

Alcohol use disorders. The spectrum of alcohol use disorders includes heavy drinking, hazardous use, harmful use, abuse, and dependence ( Table 2 ). Taking into account older adults’ physiology—these individuals have slower metabolism and smaller volume of distribution—National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcohol consumption guidelines for the elderly differ from those for younger adults.

NIAAA guidelines for the elderly define hazardous use as >3 drinks in 1 sitting or >7 drinks in 1 week for both men and women. This is in comparison with guidelines for younger adults that define hazardous use as >5 drinks in 1 sitting (or >2 drinks/day) for men and >3 drinks in 1 sitting (or >1 drink/day) for women. The NIAAA recommendation considers a standard drink to be 12 oz of beer, 5 oz of wine, or 1.5 oz of distilled spirits, each drink containing approximately 0.5 oz of alcohol.⁵

Not all screening tools developed to assess alcohol use have been studied extensively in older cohorts,⁶ and some might not be useful in certain populations.⁷ The CAGE screening tool, for example—although easy to administer and widely studied—has low sensitivity in psychiatric populations, does not address past vs current drinking problems, and does not distinguish age-specific criteria for problem drinking.

Consider using instruments specific to an older individual’s comorbidities:

• the AUDIT-5 is appropriate for an older patient with psychiatric illness
• the ARPS (or the shorter shARPS) for an older individual with medical problems is likely to improve the rate of identifying problem drinkers.

Table 1

Comparing screening tools for alcohol use disorders in the elderly

Table 2

Spectrum of alcohol use disorders: Heavy drinking to dependence

Drug abuse or medication misuse. Illegal drug use is relatively rare in the geriatric population,⁸ although the rates in patients age 50 to 59 increased from 2.7% in 2002 to 5.0% in 2007.⁹ In part this may reflect a higher lifetime use of illicit drugs by the baby boomers compared with previous generations.

Evidence also suggests an increasing risk for misuse and abuse of prescription drugs. One factor associated with this risk is medical exposure to prescription drugs with abuse potential. Among older adults in the United States:

• 10% are taking sedative-hypnotic medications
• 15% have been prescribed an opioid-analgesic medication.¹⁰

Other factors associated with prescription medication misuse and abuse by older adults include female sex, social isolation, history of substance use or psychiatric disorder, polypharmacy, and chronic medical problems.¹¹

Very few screening instruments detect illicit drug use or prescription medication abuse. To screen older patients, ask about the drugs they are using (prescription and nonprescription), ask about side effects, and look for behavioral signs of medication misuse ( Table 3 ).^12,13

Laboratory tests for alcohol’s metabolic effects can identify biologic markers of alcohol use disorders. An elevated mean corpuscular volume (MCV) or gamma-glutamyl transpeptidase (GGT) above the upper normal value can indicate possible problem drinking, even without considering total alcohol intake. Normal lab values are the same for older and younger adults.

Evidence suggests a poor association between findings of the CAGE questionnaire and MCV and GGT tests. Di Bari et al¹⁴ reported that biologic markers help identify older drinkers with compromised health status independent of a positive CAGE. This suggests that using a combination of tools to screen for psychosocial and biologic consequences could be more accurate than a single instrument in identifying older individuals with alcohol use disorders.¹⁴ We often use a GGT and MCV, along with the CAGE and the AUDIT-5 or SMAST-G.

Tobacco use. Smoking rates decrease with age, but this trend may reflect early mortality among tobacco users. Nicotine dependence remains a significant public health issue among the 7% to 9% of adults age ≥65 who smoke.¹⁵ An estimated 70% of all smokers want to quit, and 46% make an attempt each year.¹¹

The single most important step in addressing tobacco use and dependence is screening. After asking about tobacco use and assessing the patient’s willingness to quit, you can provide appropriate interventions.¹⁶

Table 3

Behavioral signs of medication misuse by elderly patients

Treatment options

General treatment options to consider for older patients with SUDs include a brief outpatient intervention, referral to a substance abuse specialist or inpatient treatment, and appropriate pharmacotherapy ( Table 4 ).

Brief interventions vary from relatively unstructured interactions in a physician’s office to more formal therapy. Components of these interventions include expression of concern, assessment and feedback, and direct advice. For older patients with SUDs, psychosocial approaches can improve treatment outcomes. One useful example—designed for alcohol use disorders—is the BRENDA model ( Table 5 ). Any trained health care staff member can administer this model, which is standardized with a comprehensive manual.¹⁷

Several brief intervention trials—including Project Guiding Older Adult Lifestyles (GOAL), the Health Profile Project, and the Staying Healthy Project—found that brief intervention results in significantly decreased alcohol consumption, sometimes even at 12-month follow-up.¹⁸ These trials were conducted in primary care settings, but brief interventions likely would be effective in psychiatric practice as well. Project GOAL included two 10- to 15-minute sessions with a physician scheduled 1 month apart and a follow-up phone call 2 weeks after each visit. The Health Profile Project consisted of a single motivational enhancement session.¹⁹

When to refer. Severe cases may require evaluation by a substance abuse specialist of the need for detoxification from alcohol, benzodiazepines, or opioids. Referral is appropriate if the patient has:

• a history of complicated withdrawal, including withdrawal seizures or delirium tremens
• complicated underlying medical conditions, such as severe coronary artery disease, uncontrolled hypertension, or uncontrolled diabetes.

Because of age-related physiologic changes, the older population is at risk for a more protracted withdrawal with more severe symptoms, compared with younger patients.²⁰ Specialized care may include detoxification (outpatient or inpatient, depending on withdrawal symptom severity), day hospital program, or—in the case of a patient with a long history of substance use and multiple relapses—a longer-term residential program.

Table 4

Recommended treatments for substance use disorders in the elderly

Table 5

The BRENDA model:
A brief psychosocial intervention for alcohol use disorders*

Pharmacotherapy

Pharmacotherapy is an important component in the treatment of older adults with SUDs. Other elements include psychosocial interventions, brief interventions, cognitive-behavioral therapies, and supportive programs such as Alcoholics Anonymous or Narcotics Anonymous. Randomized controlled trials on the use of medications for SUDs in older patients are limited. As with any other medication trial in the elderly, start with the lowest possible dose and titrate slowly to treatment effect.

Alcohol use disorders. In our experience, naltrexone—an opioid antagonist—is the first-line agent to consider for alcohol dependence in older patients ( Table 4 ). Oslin et al²¹ found naltrexone, 50 mg/d, to be well-tolerated and effective in decreasing rates of relapse to heavy drinking in older adults.

Because of its potential hepatotoxic effects, use naltrexone with caution in patients with hepatic impairment. We recommend baseline liver function tests, with repeat testing in 3 to 6 months. Severe liver disease would be a contraindication for naltrexone, but consider risk vs benefit in individual patients.

Acamprosate—a glutamatergic medication—has been studied and approved for treating alcohol dependence in adults, although no study has specifically examined its use in elderly patients. Acamprosate may offer an alternative for patients with severe liver disease or those who can’t tolerate naltrexone.

Disulfiram is rarely used in the elderly because of potential risks of hypotension and cardiovascular adverse effects in a disulfiram-ethanol reaction. Topiramate—an anticonvulsant that potentiates gamma-aminobutyric acid—has shown benefit in treating initiation of abstinence from alcohol.²² It is an incompatible treatment for the elderly, however, because it may cause cognitive impairment.

Sedative-hypnotic misuse. The goal in treating patients who misuse sedatives or hypnotics is detoxification, which usually is addressed with a gradual and slow taper under controlled supervision in the outpatient setting.

Opioid dependence. Treatment options for opioid dependence are the same whether older patients are misusing prescription opioids or illicit ones such as heroin. Naltrexone, methadone, and buprenorphine/naloxone have been widely studied and used in younger adults but only minimally in the elderly.

Studies conducted in methadone maintenance clinics have found positive results when older patients are treated for opioid dependence:

• patients age ≥55 may have fewer problems and better outcomes with opioid treatment than younger patients²³
• older age is 1 of only 2 variables (the other is no criminal justice involvement) found to be positively associated with longer duration in treatment.²⁴

Older individuals are more sensitive than younger adults to the sedation and respiratory depression of opioids. Buprenorphine is the only opioid with a ceiling effect for respiratory depression, and it does not have an increased half-life in the elderly as do other opioids.²⁵

Other potential side effects of these medications include urinary retention—particularly in elderly males with prostatic hyperplasia—constipation, and movement disorders.

Despite potential side effects, we find that opioid dependence is more successfully treated with agonist or partial agonist therapy than with blocking agents. Buprenorphine and methadone address urges and cravings to use opioids, resulting in greater treatment retention and longer abstinence. Buprenorphine treatment is available in office-based practices of physicians who have received training and certification.

Smoking cessation. Pharmacotherapy and brief treatment interventions can be effective and should be offered to the older smoker. Nicotine replacement therapy, bupropion, varenicline, and nortriptyline help improve quit rates in younger adults, but studies of these agents in older adults are limited.

If monotherapy fails, try combining shorter-acting nicotine replacement therapy with longer-acting agents such as bupropion or varenicline. To our knowledge no dosing adjustment is necessary for the elderly, although we recommend low starting doses with gradual titration.

Some literature suggests nortriptyline as a second-line smoking cessation agent in the elderly. We do not recommend nortriptyline for smoking cessation in this population, however, because of tricyclic antidepressants’ cardiac effects.

Related resources

• Schultz SK, Arndt S, Liesved J. Locations of facilities with special programs for older substance abuse clients in the U.S. Int J Geriatr Psychiatry. 2003;18(9):839-843.
• National Association of Addiction Treatment Providers. www.naatp.org.
• National Association of State Alcohol/Drug Abuse Directors. www.nasadad.org.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• American Academy of Addiction Psychiatry. www.aaap.org.

Drug brand names

• Acamprosate • Campral
• Buprenorphine/naloxone • Suboxone
• Bupropion • Zyban
• Disulfiram • Antabuse
• Methadone • Dolophine, Methadose
• Naltrexone • ReVia
• Nortriptyline • Aventyl, Pamelor
• Oxycodone • OxyContin, Roxicodone, others
• Topiramate • Topamax
• Varenicline • Chantix

Disclosure

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

Discuss this article

As the eldest post-World War II “baby boomers” turn 64 this year, relaxed social attitudes about substance use during their lifetimes may predict an increasing risk for substance use disorders (SUDs) in older Americans.¹ This presents challenges for psychiatric clinicians:

• Common screening tools used for younger patients might not adequately diagnose SUDs in patients clinically defined as elderly (age ≥65).
• DSM-IV-TR’s definition of substance use as causing clinically significant impairment or distress—such as occupational difficulties, legal problems, or decreased participation in social activities—might not apply to older patients, or these problems could be caused by other factors in older individuals.²

This article describes screening and treatment approaches shown to be most effective for identifying and managing primary SUDs in older patients. Our goal is to help you ask the right questions and provide appropriate care.

Phase-of-life issues

Most older adults have a primary care physician, but their SUDs often go unrecognized.³ Clinicians and family members might hesitate to ask about substance use or prescription medication misuse, and complications—such as falls or cognitive impairment—may be misattributed to normal aging. Thus, SUD screening of older individuals referred for psychiatric care is important.

Older adults respond with higher adherence rates when SUD treatment addresses age-specific issues—such as recent losses, medical problems, and challenges of keeping scheduled appointments or multiple providers/referrals. A combination of psychosocial and biologic treatments may be most beneficial. Although outcomes vary, some evidence indicates that age-specific programs for older alcoholics significantly improve abstinence rates at 6 and 12 months, compared with mixed-age programs⁴ ( see Related Resources ).

We recommend that you incorporate phase-of-life considerations at all stages of treatment. These include:

• education regarding lowered alcohol intake recommendations
• assessment tools that use criteria relevant to older adults
• treatment interventions that involve age-specific groups and programming.

Screening tools

In a routine office visit, a sensible approach is to screen for alcohol, tobacco, and prescription medication misuse. First-line screening tools for alcohol abuse include the AUDIT-5, CAGE, or MAST-G ( Table 1 ), accompanied by questions about medication side effects and observation of behavioral signs of medication misuse.

Alcohol use disorders. The spectrum of alcohol use disorders includes heavy drinking, hazardous use, harmful use, abuse, and dependence ( Table 2 ). Taking into account older adults’ physiology—these individuals have slower metabolism and smaller volume of distribution—National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcohol consumption guidelines for the elderly differ from those for younger adults.

NIAAA guidelines for the elderly define hazardous use as >3 drinks in 1 sitting or >7 drinks in 1 week for both men and women. This is in comparison with guidelines for younger adults that define hazardous use as >5 drinks in 1 sitting (or >2 drinks/day) for men and >3 drinks in 1 sitting (or >1 drink/day) for women. The NIAAA recommendation considers a standard drink to be 12 oz of beer, 5 oz of wine, or 1.5 oz of distilled spirits, each drink containing approximately 0.5 oz of alcohol.⁵

Not all screening tools developed to assess alcohol use have been studied extensively in older cohorts,⁶ and some might not be useful in certain populations.⁷ The CAGE screening tool, for example—although easy to administer and widely studied—has low sensitivity in psychiatric populations, does not address past vs current drinking problems, and does not distinguish age-specific criteria for problem drinking.

Consider using instruments specific to an older individual’s comorbidities:

• the AUDIT-5 is appropriate for an older patient with psychiatric illness
• the ARPS (or the shorter shARPS) for an older individual with medical problems is likely to improve the rate of identifying problem drinkers.

Table 1

Comparing screening tools for alcohol use disorders in the elderly

Table 2

Spectrum of alcohol use disorders: Heavy drinking to dependence

Drug abuse or medication misuse. Illegal drug use is relatively rare in the geriatric population,⁸ although the rates in patients age 50 to 59 increased from 2.7% in 2002 to 5.0% in 2007.⁹ In part this may reflect a higher lifetime use of illicit drugs by the baby boomers compared with previous generations.

Evidence also suggests an increasing risk for misuse and abuse of prescription drugs. One factor associated with this risk is medical exposure to prescription drugs with abuse potential. Among older adults in the United States:

• 10% are taking sedative-hypnotic medications
• 15% have been prescribed an opioid-analgesic medication.¹⁰

Other factors associated with prescription medication misuse and abuse by older adults include female sex, social isolation, history of substance use or psychiatric disorder, polypharmacy, and chronic medical problems.¹¹

Very few screening instruments detect illicit drug use or prescription medication abuse. To screen older patients, ask about the drugs they are using (prescription and nonprescription), ask about side effects, and look for behavioral signs of medication misuse ( Table 3 ).^12,13

Laboratory tests for alcohol’s metabolic effects can identify biologic markers of alcohol use disorders. An elevated mean corpuscular volume (MCV) or gamma-glutamyl transpeptidase (GGT) above the upper normal value can indicate possible problem drinking, even without considering total alcohol intake. Normal lab values are the same for older and younger adults.

Evidence suggests a poor association between findings of the CAGE questionnaire and MCV and GGT tests. Di Bari et al¹⁴ reported that biologic markers help identify older drinkers with compromised health status independent of a positive CAGE. This suggests that using a combination of tools to screen for psychosocial and biologic consequences could be more accurate than a single instrument in identifying older individuals with alcohol use disorders.¹⁴ We often use a GGT and MCV, along with the CAGE and the AUDIT-5 or SMAST-G.

Tobacco use. Smoking rates decrease with age, but this trend may reflect early mortality among tobacco users. Nicotine dependence remains a significant public health issue among the 7% to 9% of adults age ≥65 who smoke.¹⁵ An estimated 70% of all smokers want to quit, and 46% make an attempt each year.¹¹

The single most important step in addressing tobacco use and dependence is screening. After asking about tobacco use and assessing the patient’s willingness to quit, you can provide appropriate interventions.¹⁶

Table 3

Behavioral signs of medication misuse by elderly patients

Treatment options

General treatment options to consider for older patients with SUDs include a brief outpatient intervention, referral to a substance abuse specialist or inpatient treatment, and appropriate pharmacotherapy ( Table 4 ).

Brief interventions vary from relatively unstructured interactions in a physician’s office to more formal therapy. Components of these interventions include expression of concern, assessment and feedback, and direct advice. For older patients with SUDs, psychosocial approaches can improve treatment outcomes. One useful example—designed for alcohol use disorders—is the BRENDA model ( Table 5 ). Any trained health care staff member can administer this model, which is standardized with a comprehensive manual.¹⁷

Several brief intervention trials—including Project Guiding Older Adult Lifestyles (GOAL), the Health Profile Project, and the Staying Healthy Project—found that brief intervention results in significantly decreased alcohol consumption, sometimes even at 12-month follow-up.¹⁸ These trials were conducted in primary care settings, but brief interventions likely would be effective in psychiatric practice as well. Project GOAL included two 10- to 15-minute sessions with a physician scheduled 1 month apart and a follow-up phone call 2 weeks after each visit. The Health Profile Project consisted of a single motivational enhancement session.¹⁹

When to refer. Severe cases may require evaluation by a substance abuse specialist of the need for detoxification from alcohol, benzodiazepines, or opioids. Referral is appropriate if the patient has:

• a history of complicated withdrawal, including withdrawal seizures or delirium tremens
• complicated underlying medical conditions, such as severe coronary artery disease, uncontrolled hypertension, or uncontrolled diabetes.

Because of age-related physiologic changes, the older population is at risk for a more protracted withdrawal with more severe symptoms, compared with younger patients.²⁰ Specialized care may include detoxification (outpatient or inpatient, depending on withdrawal symptom severity), day hospital program, or—in the case of a patient with a long history of substance use and multiple relapses—a longer-term residential program.

Table 4

Recommended treatments for substance use disorders in the elderly

Table 5

The BRENDA model:
A brief psychosocial intervention for alcohol use disorders*

Pharmacotherapy

Pharmacotherapy is an important component in the treatment of older adults with SUDs. Other elements include psychosocial interventions, brief interventions, cognitive-behavioral therapies, and supportive programs such as Alcoholics Anonymous or Narcotics Anonymous. Randomized controlled trials on the use of medications for SUDs in older patients are limited. As with any other medication trial in the elderly, start with the lowest possible dose and titrate slowly to treatment effect.

Alcohol use disorders. In our experience, naltrexone—an opioid antagonist—is the first-line agent to consider for alcohol dependence in older patients ( Table 4 ). Oslin et al²¹ found naltrexone, 50 mg/d, to be well-tolerated and effective in decreasing rates of relapse to heavy drinking in older adults.

Because of its potential hepatotoxic effects, use naltrexone with caution in patients with hepatic impairment. We recommend baseline liver function tests, with repeat testing in 3 to 6 months. Severe liver disease would be a contraindication for naltrexone, but consider risk vs benefit in individual patients.

Acamprosate—a glutamatergic medication—has been studied and approved for treating alcohol dependence in adults, although no study has specifically examined its use in elderly patients. Acamprosate may offer an alternative for patients with severe liver disease or those who can’t tolerate naltrexone.

Disulfiram is rarely used in the elderly because of potential risks of hypotension and cardiovascular adverse effects in a disulfiram-ethanol reaction. Topiramate—an anticonvulsant that potentiates gamma-aminobutyric acid—has shown benefit in treating initiation of abstinence from alcohol.²² It is an incompatible treatment for the elderly, however, because it may cause cognitive impairment.

Sedative-hypnotic misuse. The goal in treating patients who misuse sedatives or hypnotics is detoxification, which usually is addressed with a gradual and slow taper under controlled supervision in the outpatient setting.

Opioid dependence. Treatment options for opioid dependence are the same whether older patients are misusing prescription opioids or illicit ones such as heroin. Naltrexone, methadone, and buprenorphine/naloxone have been widely studied and used in younger adults but only minimally in the elderly.

Studies conducted in methadone maintenance clinics have found positive results when older patients are treated for opioid dependence:

• patients age ≥55 may have fewer problems and better outcomes with opioid treatment than younger patients²³
• older age is 1 of only 2 variables (the other is no criminal justice involvement) found to be positively associated with longer duration in treatment.²⁴

Older individuals are more sensitive than younger adults to the sedation and respiratory depression of opioids. Buprenorphine is the only opioid with a ceiling effect for respiratory depression, and it does not have an increased half-life in the elderly as do other opioids.²⁵

Other potential side effects of these medications include urinary retention—particularly in elderly males with prostatic hyperplasia—constipation, and movement disorders.

Despite potential side effects, we find that opioid dependence is more successfully treated with agonist or partial agonist therapy than with blocking agents. Buprenorphine and methadone address urges and cravings to use opioids, resulting in greater treatment retention and longer abstinence. Buprenorphine treatment is available in office-based practices of physicians who have received training and certification.

Smoking cessation. Pharmacotherapy and brief treatment interventions can be effective and should be offered to the older smoker. Nicotine replacement therapy, bupropion, varenicline, and nortriptyline help improve quit rates in younger adults, but studies of these agents in older adults are limited.

If monotherapy fails, try combining shorter-acting nicotine replacement therapy with longer-acting agents such as bupropion or varenicline. To our knowledge no dosing adjustment is necessary for the elderly, although we recommend low starting doses with gradual titration.

Some literature suggests nortriptyline as a second-line smoking cessation agent in the elderly. We do not recommend nortriptyline for smoking cessation in this population, however, because of tricyclic antidepressants’ cardiac effects.

Related resources

• Schultz SK, Arndt S, Liesved J. Locations of facilities with special programs for older substance abuse clients in the U.S. Int J Geriatr Psychiatry. 2003;18(9):839-843.
• National Association of Addiction Treatment Providers. www.naatp.org.
• National Association of State Alcohol/Drug Abuse Directors. www.nasadad.org.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• American Academy of Addiction Psychiatry. www.aaap.org.

Drug brand names

• Acamprosate • Campral
• Buprenorphine/naloxone • Suboxone
• Bupropion • Zyban
• Disulfiram • Antabuse
• Methadone • Dolophine, Methadose
• Naltrexone • ReVia
• Nortriptyline • Aventyl, Pamelor
• Oxycodone • OxyContin, Roxicodone, others
• Topiramate • Topamax
• Varenicline • Chantix

Disclosure

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

Discuss this article

As the eldest post-World War II “baby boomers” turn 64 this year, relaxed social attitudes about substance use during their lifetimes may predict an increasing risk for substance use disorders (SUDs) in older Americans.¹ This presents challenges for psychiatric clinicians:

• Common screening tools used for younger patients might not adequately diagnose SUDs in patients clinically defined as elderly (age ≥65).
• DSM-IV-TR’s definition of substance use as causing clinically significant impairment or distress—such as occupational difficulties, legal problems, or decreased participation in social activities—might not apply to older patients, or these problems could be caused by other factors in older individuals.²

This article describes screening and treatment approaches shown to be most effective for identifying and managing primary SUDs in older patients. Our goal is to help you ask the right questions and provide appropriate care.

Phase-of-life issues

Most older adults have a primary care physician, but their SUDs often go unrecognized.³ Clinicians and family members might hesitate to ask about substance use or prescription medication misuse, and complications—such as falls or cognitive impairment—may be misattributed to normal aging. Thus, SUD screening of older individuals referred for psychiatric care is important.

Older adults respond with higher adherence rates when SUD treatment addresses age-specific issues—such as recent losses, medical problems, and challenges of keeping scheduled appointments or multiple providers/referrals. A combination of psychosocial and biologic treatments may be most beneficial. Although outcomes vary, some evidence indicates that age-specific programs for older alcoholics significantly improve abstinence rates at 6 and 12 months, compared with mixed-age programs⁴ ( see Related Resources ).

We recommend that you incorporate phase-of-life considerations at all stages of treatment. These include:

• education regarding lowered alcohol intake recommendations
• assessment tools that use criteria relevant to older adults
• treatment interventions that involve age-specific groups and programming.

Screening tools

In a routine office visit, a sensible approach is to screen for alcohol, tobacco, and prescription medication misuse. First-line screening tools for alcohol abuse include the AUDIT-5, CAGE, or MAST-G ( Table 1 ), accompanied by questions about medication side effects and observation of behavioral signs of medication misuse.

Alcohol use disorders. The spectrum of alcohol use disorders includes heavy drinking, hazardous use, harmful use, abuse, and dependence ( Table 2 ). Taking into account older adults’ physiology—these individuals have slower metabolism and smaller volume of distribution—National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcohol consumption guidelines for the elderly differ from those for younger adults.

NIAAA guidelines for the elderly define hazardous use as >3 drinks in 1 sitting or >7 drinks in 1 week for both men and women. This is in comparison with guidelines for younger adults that define hazardous use as >5 drinks in 1 sitting (or >2 drinks/day) for men and >3 drinks in 1 sitting (or >1 drink/day) for women. The NIAAA recommendation considers a standard drink to be 12 oz of beer, 5 oz of wine, or 1.5 oz of distilled spirits, each drink containing approximately 0.5 oz of alcohol.⁵

Not all screening tools developed to assess alcohol use have been studied extensively in older cohorts,⁶ and some might not be useful in certain populations.⁷ The CAGE screening tool, for example—although easy to administer and widely studied—has low sensitivity in psychiatric populations, does not address past vs current drinking problems, and does not distinguish age-specific criteria for problem drinking.

Consider using instruments specific to an older individual’s comorbidities:

• the AUDIT-5 is appropriate for an older patient with psychiatric illness
• the ARPS (or the shorter shARPS) for an older individual with medical problems is likely to improve the rate of identifying problem drinkers.

Table 1

Comparing screening tools for alcohol use disorders in the elderly

Table 2

Spectrum of alcohol use disorders: Heavy drinking to dependence

Drug abuse or medication misuse. Illegal drug use is relatively rare in the geriatric population,⁸ although the rates in patients age 50 to 59 increased from 2.7% in 2002 to 5.0% in 2007.⁹ In part this may reflect a higher lifetime use of illicit drugs by the baby boomers compared with previous generations.

Evidence also suggests an increasing risk for misuse and abuse of prescription drugs. One factor associated with this risk is medical exposure to prescription drugs with abuse potential. Among older adults in the United States:

• 10% are taking sedative-hypnotic medications
• 15% have been prescribed an opioid-analgesic medication.¹⁰

Other factors associated with prescription medication misuse and abuse by older adults include female sex, social isolation, history of substance use or psychiatric disorder, polypharmacy, and chronic medical problems.¹¹

Very few screening instruments detect illicit drug use or prescription medication abuse. To screen older patients, ask about the drugs they are using (prescription and nonprescription), ask about side effects, and look for behavioral signs of medication misuse ( Table 3 ).^12,13

Laboratory tests for alcohol’s metabolic effects can identify biologic markers of alcohol use disorders. An elevated mean corpuscular volume (MCV) or gamma-glutamyl transpeptidase (GGT) above the upper normal value can indicate possible problem drinking, even without considering total alcohol intake. Normal lab values are the same for older and younger adults.

Evidence suggests a poor association between findings of the CAGE questionnaire and MCV and GGT tests. Di Bari et al¹⁴ reported that biologic markers help identify older drinkers with compromised health status independent of a positive CAGE. This suggests that using a combination of tools to screen for psychosocial and biologic consequences could be more accurate than a single instrument in identifying older individuals with alcohol use disorders.¹⁴ We often use a GGT and MCV, along with the CAGE and the AUDIT-5 or SMAST-G.

Tobacco use. Smoking rates decrease with age, but this trend may reflect early mortality among tobacco users. Nicotine dependence remains a significant public health issue among the 7% to 9% of adults age ≥65 who smoke.¹⁵ An estimated 70% of all smokers want to quit, and 46% make an attempt each year.¹¹

The single most important step in addressing tobacco use and dependence is screening. After asking about tobacco use and assessing the patient’s willingness to quit, you can provide appropriate interventions.¹⁶

Table 3

Behavioral signs of medication misuse by elderly patients

Treatment options

General treatment options to consider for older patients with SUDs include a brief outpatient intervention, referral to a substance abuse specialist or inpatient treatment, and appropriate pharmacotherapy ( Table 4 ).

Brief interventions vary from relatively unstructured interactions in a physician’s office to more formal therapy. Components of these interventions include expression of concern, assessment and feedback, and direct advice. For older patients with SUDs, psychosocial approaches can improve treatment outcomes. One useful example—designed for alcohol use disorders—is the BRENDA model ( Table 5 ). Any trained health care staff member can administer this model, which is standardized with a comprehensive manual.¹⁷

Several brief intervention trials—including Project Guiding Older Adult Lifestyles (GOAL), the Health Profile Project, and the Staying Healthy Project—found that brief intervention results in significantly decreased alcohol consumption, sometimes even at 12-month follow-up.¹⁸ These trials were conducted in primary care settings, but brief interventions likely would be effective in psychiatric practice as well. Project GOAL included two 10- to 15-minute sessions with a physician scheduled 1 month apart and a follow-up phone call 2 weeks after each visit. The Health Profile Project consisted of a single motivational enhancement session.¹⁹

When to refer. Severe cases may require evaluation by a substance abuse specialist of the need for detoxification from alcohol, benzodiazepines, or opioids. Referral is appropriate if the patient has:

• a history of complicated withdrawal, including withdrawal seizures or delirium tremens
• complicated underlying medical conditions, such as severe coronary artery disease, uncontrolled hypertension, or uncontrolled diabetes.

Because of age-related physiologic changes, the older population is at risk for a more protracted withdrawal with more severe symptoms, compared with younger patients.²⁰ Specialized care may include detoxification (outpatient or inpatient, depending on withdrawal symptom severity), day hospital program, or—in the case of a patient with a long history of substance use and multiple relapses—a longer-term residential program.

Table 4

Recommended treatments for substance use disorders in the elderly

Table 5

The BRENDA model:
A brief psychosocial intervention for alcohol use disorders*

Pharmacotherapy

Pharmacotherapy is an important component in the treatment of older adults with SUDs. Other elements include psychosocial interventions, brief interventions, cognitive-behavioral therapies, and supportive programs such as Alcoholics Anonymous or Narcotics Anonymous. Randomized controlled trials on the use of medications for SUDs in older patients are limited. As with any other medication trial in the elderly, start with the lowest possible dose and titrate slowly to treatment effect.

Alcohol use disorders. In our experience, naltrexone—an opioid antagonist—is the first-line agent to consider for alcohol dependence in older patients ( Table 4 ). Oslin et al²¹ found naltrexone, 50 mg/d, to be well-tolerated and effective in decreasing rates of relapse to heavy drinking in older adults.

Because of its potential hepatotoxic effects, use naltrexone with caution in patients with hepatic impairment. We recommend baseline liver function tests, with repeat testing in 3 to 6 months. Severe liver disease would be a contraindication for naltrexone, but consider risk vs benefit in individual patients.

Acamprosate—a glutamatergic medication—has been studied and approved for treating alcohol dependence in adults, although no study has specifically examined its use in elderly patients. Acamprosate may offer an alternative for patients with severe liver disease or those who can’t tolerate naltrexone.

Disulfiram is rarely used in the elderly because of potential risks of hypotension and cardiovascular adverse effects in a disulfiram-ethanol reaction. Topiramate—an anticonvulsant that potentiates gamma-aminobutyric acid—has shown benefit in treating initiation of abstinence from alcohol.²² It is an incompatible treatment for the elderly, however, because it may cause cognitive impairment.

Sedative-hypnotic misuse. The goal in treating patients who misuse sedatives or hypnotics is detoxification, which usually is addressed with a gradual and slow taper under controlled supervision in the outpatient setting.

Opioid dependence. Treatment options for opioid dependence are the same whether older patients are misusing prescription opioids or illicit ones such as heroin. Naltrexone, methadone, and buprenorphine/naloxone have been widely studied and used in younger adults but only minimally in the elderly.

Studies conducted in methadone maintenance clinics have found positive results when older patients are treated for opioid dependence:

• patients age ≥55 may have fewer problems and better outcomes with opioid treatment than younger patients²³
• older age is 1 of only 2 variables (the other is no criminal justice involvement) found to be positively associated with longer duration in treatment.²⁴

Older individuals are more sensitive than younger adults to the sedation and respiratory depression of opioids. Buprenorphine is the only opioid with a ceiling effect for respiratory depression, and it does not have an increased half-life in the elderly as do other opioids.²⁵

Other potential side effects of these medications include urinary retention—particularly in elderly males with prostatic hyperplasia—constipation, and movement disorders.

Despite potential side effects, we find that opioid dependence is more successfully treated with agonist or partial agonist therapy than with blocking agents. Buprenorphine and methadone address urges and cravings to use opioids, resulting in greater treatment retention and longer abstinence. Buprenorphine treatment is available in office-based practices of physicians who have received training and certification.

Smoking cessation. Pharmacotherapy and brief treatment interventions can be effective and should be offered to the older smoker. Nicotine replacement therapy, bupropion, varenicline, and nortriptyline help improve quit rates in younger adults, but studies of these agents in older adults are limited.

If monotherapy fails, try combining shorter-acting nicotine replacement therapy with longer-acting agents such as bupropion or varenicline. To our knowledge no dosing adjustment is necessary for the elderly, although we recommend low starting doses with gradual titration.

Some literature suggests nortriptyline as a second-line smoking cessation agent in the elderly. We do not recommend nortriptyline for smoking cessation in this population, however, because of tricyclic antidepressants’ cardiac effects.

Related resources

• Schultz SK, Arndt S, Liesved J. Locations of facilities with special programs for older substance abuse clients in the U.S. Int J Geriatr Psychiatry. 2003;18(9):839-843.
• National Association of Addiction Treatment Providers. www.naatp.org.
• National Association of State Alcohol/Drug Abuse Directors. www.nasadad.org.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• American Academy of Addiction Psychiatry. www.aaap.org.

Drug brand names