Somatic Disorders

Dizziness is common among patients age 65 and older, and more than one-third have a psychiatric disorder that is caused by or is causing their dizziness.¹

When older patients present with dizziness, psychiatrists may be asked to alleviate the psychological symptoms and help identify the underlying disease state.²

More than 60 medical and psychiatric disorders and many medications can cause dizziness. To help you sort through the possibilities, we offer:

• six diagnostic questions to rule out underlying medical problems
• lists of commonly used psychotropics and other drugs that may cause dizziness
• advice on treating depression, anxiety, and panic disorder in an older patient with dizziness while avoiding side effects and drug interactions.

Table 1

Four types of dizziness and their usual causes

Many causes of dizziness

The term “dizziness” is hard to define because of its nonspecific and variable symptom description, multiple causes, and lack of clear diagnostic and management guidelines. In clinical use, dizziness encompasses abnormal sensations relating to perception of the body’s relationship to space.

Some researchers believe dizziness is a distinct geriatric syndrome because numerous factors related to aging cause dizziness,² including physiologic changes (presbystasis), accumulated impairment, disease states, and interactions between multiple medications.

Anxiety, somatization, panic disorder, and depression cause dizziness in the elderly, as do:

• peripheral vestibular disorders
• brainstem cerebrovascular accident
• diabetes mellitus
• neurologic disorders such as Parkinson’s disease
• and cardiovascular disorders.

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants also have been shown to cause dizziness, as have numerous nonpsychotropic agents.

Recognizing patterns, testing hypotheses, and extending the diagnostic process over time can help you differentiate psychogenic from medicationinduced or neurologic dizziness.³ Because the presentation is so complex and the differential diagnosis so broad, algorithmic diagnosis is less effective than a flexible clinical approach that allows for uncertainty in evaluating initial symptoms.

Determining the cause

A thorough patient history and physical examination can uncover a cause of dizziness in 75% of cases.⁴ Look for duration of dizziness symptoms; history of heart disease, diabetes or other illnesses; family history of psychiatric disorders; and other illnesses among family members.

Ask the following six complaint-specific questions to help you narrow the differential diagnosis and rule out nonpsychiatric causes.⁵

1. WHAT TYPE OF DIZZINESS DOES THE PATIENT HAVE?

Four categories—vertigo, presyncope, disequilibrium, and lightheadedness—are used to classify dizziness (Table 1).⁶

Vertigo is a sense that the body or environment is Patients may feel as if the floor is tilting, sinking, rising or veering sideways, or they may feel pulled to one side.

Vertigo is commonly caused by peripheral vestibular disorders—including benign positional vertigo, Meniere’s disease, labyrinthitis, and vestibular neuronitis—and central vestibular disorders associated with cerebrovascular disease, tumors, demyelinating diseases, migraines, seizures, multiple sclerosis and other CNS diseases. Acute-onset vertigo and neurologic signs suggest brainstem infarction.

Nystagmus is usually present, horizontal, and may be rotational at times. A vertical-beating nystagmus points to a probable CNS cause and requires urgent neuroimaging and referral to a neurologist or otolaryngologist.

Presyncope describes near-fainting. A dimming of vision and roaring in the ears may precede presyncope.

Depending on its cause, presyncope may occur regardless of position or only when upright. Common causes include orthostatic hypotension, neurocardiogenic syncope, organic heart disease, arrhythmias, carotid sinus disease, seizures, hypoglycemia, and transient ischemic attacks.

Abrupt presyncopal attacks that occur regardless of position suggest a cardiovascular cause. If onset is gradual and not improved by lying down, suspect a cerebral metabolic cause such as hypoglycemia.

Syncope, like presyncope, often is traced to an underlying cardiovascular disease. Dizziness and syncope often coexist, and both can be multifactorial. Dizziness may precede or follow syncopal episodes.

Differentiating syncope and dizziness is important because many underlying causes of syncope can be fatal. By contrast, dizziness symptoms are usually benign and self-limiting.⁷

A thorough history is critical to distinguishing dizziness from presyncope. Assess medication effects—especially CNS-acting medications, cardiovascular drugs, antihypertensives, antibiotics, and over-the-counter medications such as dextromethorphan and acetaminophen compounds. Also check for dehydration.

Disequilibrium disorder signifies unsteadiness or a loss of balance primarily involving the lower extremities. Symptoms are evoked by walking or standing and relieved by sitting or lying down. Gait is abnormal and balance is compromised without abnormal head sensations.

Common causes include balance and gait disorders, sensorimotor dysfunction, presbystasis, neurodegenerative CNS disorders, and mixed ischemic and degenerative CNS diseases.

Vague lightheadedness is often associated with somatic symptoms such as headache. Some patients describe a floating sensation.

Lightheadedness is frequently associated with anxiety, panic disorder, depression, and somatization. Hyperventilation and agoraphobia are other common causes.

Multiple symptoms, multiple types. Classifying an older patient’s dizziness can be challenging because many patients report symptoms that suggest two or more subtypes.² Also, patients often have trouble describing their dizziness symptoms, sometimes using terms such as “giddiness,” “wooziness,” or “confusion.”

To help patients explain dizziness symptoms more accurately, ask specific questions such as:

• Do you at times feel like you’re about to faint?
• Do you feel as if the room is moving?
• Do you sometimes feel as though you’re going to fall?

Table 2

Psychotropics that may cause dizziness

2. HOW DO DIZZINESS SYMPTOMS RELATE TO POSITION OR MOTION?

By reproducing dizziness symptoms, some quick-maneuver tests can help patients describe their symptoms and may reveal a medical cause.

Dix-Hallpike maneuver.³ Move the patient rapidly from a seated to prone position with the head below the horizontal plane and turned 45 degrees for 10 seconds; then have the patient sit up. Repeat with the head turned to the other side. If dizziness does not occur within a few seconds after each test, rule out benign positional vertigo.

Seated head turn, or head-thrust test, measures qualitative vestibular function.⁸ Move the head rapidly by 45 degrees in a brief, small-amplitude thrust to one side while the patient focuses on your nose; this gauges vestibularocular control. Repeat the test in the other direction. A refixation corrective saccade, occurring as the patient tries to fixate on the target, indicates a possible vestibular disorder.

‘Get-Up and Go’ test, which takes less than 10 seconds, measures balance in older patents.⁹ Have the patient stand up, walk 10 feet, turn around, walk back, and sit down. Watch for staggering, unsteadiness, and use of hands to balance. Onset of symptoms suggests dizziness brought on during activities of daily living and provides information on how dizziness is affecting the patient’s ability to function.

Romberg test. Have the patient stand with heels together, first with eyes open and then closed. Vision and proprioceptive signals are used to compensate for vestibular loss. Thus, a balance disturbance with eyes closed suggests vestibular or spinal proprioceptive problems and may predict risk of falls caused by inability to compensate.⁸

3. WHAT IS THE COURSE OF DIZZINESS?

Differentiating acute, sudden-onset dizziness from chronic, gradual-onset dizziness can help uncover the problem’s cause and seriousness. The latter often has a psychological cause or may point to vestibular or minor cardiovascular problems. Tinetti et al² identified anxiety or depressive symptoms as risk factors among community-based older persons who reported dizziness episodes lasting 1 month.

Table 3

Recommended SSRI starting dosages for older patients

An acute presentation can suggest a panic disorder or acute anxiety state, but first rule out serious conditions such as acute myocardial infarction, arrhythmias, acute infections, GI bleeding, and carbon monoxide poisoning.

Also ask about:

• exacerbating and relieving factors. For example, positional changes, exercise or other physical activity, eating, or missing a meal can trigger presyncope. Also find out about situations that may bring on anxiety, panic, or phobia. Onset of dizziness following these situations may suggest psychogenesis.
• recent falls and injuries. Recurrent falls with presyncope suggest a probable orthostatic or cardiovascular diagnosis in older adults.

4. ANY PAST MEDICAL PROBLEMS?

Ask disease-specific questions. For example:

• Tinnitus or hearing loss could point to a vestibular disorder.
• Metabolic and cardiovascular disorders such as diabetes, ischemic heart disease, postural hypotension, and seizures can result in presyncope.
• Orthostasis, coronary ischemic events, hypoglycemia, and transient ischemic attacks may cause dizziness.

5. IS DIZZINESS RECURRENT?

Panic disorder, anxiety disorders, phobia, and psychogenic hyperventilation are commonly associated with chronic, recurrent dizziness episodes.

6. WHAT MEDICATIONS IS THE PATIENT TAKING?

All psychotropics are suspect when a patient presents with dizziness. When dizziness occurs after a dose or start of therapy, evaluate response to the medication and consider reducing the dosage or changing the medication. If symptoms persist, refer the patient back to the primary care physician to investigate for other causes of dizziness.

Psychotropics that may cause dizziness are listed in Table 2, For a list of other medications associated with dizziness, see this article at www.currentpsychiatry.com.

If the above strategies do not reveal a physical cause of dizziness despite multiple physical complaints, consider examining the patient for depression, anxiety, or panic disorder.

Treating a psychiatric cause

If dizziness is found to be psychogenic and the symptoms impede daily activities or contribute to functional decline, treat the psychiatric disorder but carefully weigh the risks and benefits of drug treatment.

Although SSRIs may cause dizziness, these agents are recommended first-line treatment for depression, anxiety, and/or phobia in older patients with dizziness because of their relative lack of anticholinergic action and side effects compared with other antidepressants or anxiolytics.

Coexisting medical symptoms may dictate choice of agent. For example, consider a sedating SSRI for a patient with sleep disturbances caused by dizziness or the psychiatric disorder; choose a nonsedating SSRI if the patient is sleeping normally.

Because SSRIs may cause weight loss, avoid giving them to patients with weight loss associated with dizziness or an underlying psychiatric illness. Mirtazapine, which is associated with weight gain, may offset weight loss. Start mirtazapine at 15 mg at bedtime for older patients.

Start low and go slow when prescribing an SSRI to an older patient. Dosing strategies applicable to younger patients should not be extrapolated to older patients, especially those with dizziness.

We have found that older patients respond well to minimum or below-normal SSRI dosages (Table 3). Titrate very slowly and instruct patients to report dizziness. Reduce the dosage if dizziness emerges.

If the patient does not respond to an SSRI or mirtazapine, consider a serotonin and norepinephrine reuptake inhibitor, which also has favorable anticholinergic and side-effect profiles.

Related resources

• WebMD Health—Dizziness: lightheadedness and vertigo. http://my.webMD.com/hw/health_guide_atoz/hw88500.asp.
• Sloane PD. Clinical research and geriatric dizziness: The blind men and the elephant. J Am Geriatr Soc 1999;47:113-14.
• Kroenke K, Hoffman RM, Einstadter D. How common are various forms of dizziness? A critical review. South Med J 2000;93:160-7.

Drug brand names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Chlordiazepoxide • Librium
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clonazepam • Klonopin
• Diazepam • Valium
• Divalproex/valproic acid • Depakote
• Escitalopram • Lexapro
• Estazolam • ProSom
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Flurazepam • Dalmane
• Gabapentin • Neurontin
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Memantine • Namenda
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenelzine • Nardil
• Phenytoin • Dilantin
• Prochlorperazine • Compazine
• Quazepam • Doral
• Rivastigmine • Exelon
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Tacrine • Cognex
• Temazepam • Restoril
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Triazolam • Halcion
• Trifluoperazine • Vesprin
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosure

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

Acknowledgment

The authors thank Robert Cluxton, PharmD, University of Cincinnati College of Pharmacy, for helping to prepare this manuscript for publication.

Dizziness is common among patients age 65 and older, and more than one-third have a psychiatric disorder that is caused by or is causing their dizziness.¹

When older patients present with dizziness, psychiatrists may be asked to alleviate the psychological symptoms and help identify the underlying disease state.²

More than 60 medical and psychiatric disorders and many medications can cause dizziness. To help you sort through the possibilities, we offer:

• six diagnostic questions to rule out underlying medical problems
• lists of commonly used psychotropics and other drugs that may cause dizziness
• advice on treating depression, anxiety, and panic disorder in an older patient with dizziness while avoiding side effects and drug interactions.

Table 1

Four types of dizziness and their usual causes

Many causes of dizziness

The term “dizziness” is hard to define because of its nonspecific and variable symptom description, multiple causes, and lack of clear diagnostic and management guidelines. In clinical use, dizziness encompasses abnormal sensations relating to perception of the body’s relationship to space.

Some researchers believe dizziness is a distinct geriatric syndrome because numerous factors related to aging cause dizziness,² including physiologic changes (presbystasis), accumulated impairment, disease states, and interactions between multiple medications.

Anxiety, somatization, panic disorder, and depression cause dizziness in the elderly, as do:

• peripheral vestibular disorders
• brainstem cerebrovascular accident
• diabetes mellitus
• neurologic disorders such as Parkinson’s disease
• and cardiovascular disorders.

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants also have been shown to cause dizziness, as have numerous nonpsychotropic agents.

Recognizing patterns, testing hypotheses, and extending the diagnostic process over time can help you differentiate psychogenic from medicationinduced or neurologic dizziness.³ Because the presentation is so complex and the differential diagnosis so broad, algorithmic diagnosis is less effective than a flexible clinical approach that allows for uncertainty in evaluating initial symptoms.

Determining the cause

A thorough patient history and physical examination can uncover a cause of dizziness in 75% of cases.⁴ Look for duration of dizziness symptoms; history of heart disease, diabetes or other illnesses; family history of psychiatric disorders; and other illnesses among family members.

Ask the following six complaint-specific questions to help you narrow the differential diagnosis and rule out nonpsychiatric causes.⁵

1. WHAT TYPE OF DIZZINESS DOES THE PATIENT HAVE?

Four categories—vertigo, presyncope, disequilibrium, and lightheadedness—are used to classify dizziness (Table 1).⁶

Vertigo is a sense that the body or environment is Patients may feel as if the floor is tilting, sinking, rising or veering sideways, or they may feel pulled to one side.

Vertigo is commonly caused by peripheral vestibular disorders—including benign positional vertigo, Meniere’s disease, labyrinthitis, and vestibular neuronitis—and central vestibular disorders associated with cerebrovascular disease, tumors, demyelinating diseases, migraines, seizures, multiple sclerosis and other CNS diseases. Acute-onset vertigo and neurologic signs suggest brainstem infarction.

Nystagmus is usually present, horizontal, and may be rotational at times. A vertical-beating nystagmus points to a probable CNS cause and requires urgent neuroimaging and referral to a neurologist or otolaryngologist.

Presyncope describes near-fainting. A dimming of vision and roaring in the ears may precede presyncope.

Depending on its cause, presyncope may occur regardless of position or only when upright. Common causes include orthostatic hypotension, neurocardiogenic syncope, organic heart disease, arrhythmias, carotid sinus disease, seizures, hypoglycemia, and transient ischemic attacks.

Abrupt presyncopal attacks that occur regardless of position suggest a cardiovascular cause. If onset is gradual and not improved by lying down, suspect a cerebral metabolic cause such as hypoglycemia.

Syncope, like presyncope, often is traced to an underlying cardiovascular disease. Dizziness and syncope often coexist, and both can be multifactorial. Dizziness may precede or follow syncopal episodes.

Differentiating syncope and dizziness is important because many underlying causes of syncope can be fatal. By contrast, dizziness symptoms are usually benign and self-limiting.⁷

A thorough history is critical to distinguishing dizziness from presyncope. Assess medication effects—especially CNS-acting medications, cardiovascular drugs, antihypertensives, antibiotics, and over-the-counter medications such as dextromethorphan and acetaminophen compounds. Also check for dehydration.

Disequilibrium disorder signifies unsteadiness or a loss of balance primarily involving the lower extremities. Symptoms are evoked by walking or standing and relieved by sitting or lying down. Gait is abnormal and balance is compromised without abnormal head sensations.

Common causes include balance and gait disorders, sensorimotor dysfunction, presbystasis, neurodegenerative CNS disorders, and mixed ischemic and degenerative CNS diseases.

Vague lightheadedness is often associated with somatic symptoms such as headache. Some patients describe a floating sensation.

Lightheadedness is frequently associated with anxiety, panic disorder, depression, and somatization. Hyperventilation and agoraphobia are other common causes.

Multiple symptoms, multiple types. Classifying an older patient’s dizziness can be challenging because many patients report symptoms that suggest two or more subtypes.² Also, patients often have trouble describing their dizziness symptoms, sometimes using terms such as “giddiness,” “wooziness,” or “confusion.”

To help patients explain dizziness symptoms more accurately, ask specific questions such as:

• Do you at times feel like you’re about to faint?
• Do you feel as if the room is moving?
• Do you sometimes feel as though you’re going to fall?

Table 2

Psychotropics that may cause dizziness

2. HOW DO DIZZINESS SYMPTOMS RELATE TO POSITION OR MOTION?

By reproducing dizziness symptoms, some quick-maneuver tests can help patients describe their symptoms and may reveal a medical cause.

Dix-Hallpike maneuver.³ Move the patient rapidly from a seated to prone position with the head below the horizontal plane and turned 45 degrees for 10 seconds; then have the patient sit up. Repeat with the head turned to the other side. If dizziness does not occur within a few seconds after each test, rule out benign positional vertigo.

Seated head turn, or head-thrust test, measures qualitative vestibular function.⁸ Move the head rapidly by 45 degrees in a brief, small-amplitude thrust to one side while the patient focuses on your nose; this gauges vestibularocular control. Repeat the test in the other direction. A refixation corrective saccade, occurring as the patient tries to fixate on the target, indicates a possible vestibular disorder.

‘Get-Up and Go’ test, which takes less than 10 seconds, measures balance in older patents.⁹ Have the patient stand up, walk 10 feet, turn around, walk back, and sit down. Watch for staggering, unsteadiness, and use of hands to balance. Onset of symptoms suggests dizziness brought on during activities of daily living and provides information on how dizziness is affecting the patient’s ability to function.

Romberg test. Have the patient stand with heels together, first with eyes open and then closed. Vision and proprioceptive signals are used to compensate for vestibular loss. Thus, a balance disturbance with eyes closed suggests vestibular or spinal proprioceptive problems and may predict risk of falls caused by inability to compensate.⁸

3. WHAT IS THE COURSE OF DIZZINESS?

Differentiating acute, sudden-onset dizziness from chronic, gradual-onset dizziness can help uncover the problem’s cause and seriousness. The latter often has a psychological cause or may point to vestibular or minor cardiovascular problems. Tinetti et al² identified anxiety or depressive symptoms as risk factors among community-based older persons who reported dizziness episodes lasting 1 month.

Table 3

Recommended SSRI starting dosages for older patients

An acute presentation can suggest a panic disorder or acute anxiety state, but first rule out serious conditions such as acute myocardial infarction, arrhythmias, acute infections, GI bleeding, and carbon monoxide poisoning.

Also ask about:

• exacerbating and relieving factors. For example, positional changes, exercise or other physical activity, eating, or missing a meal can trigger presyncope. Also find out about situations that may bring on anxiety, panic, or phobia. Onset of dizziness following these situations may suggest psychogenesis.
• recent falls and injuries. Recurrent falls with presyncope suggest a probable orthostatic or cardiovascular diagnosis in older adults.

4. ANY PAST MEDICAL PROBLEMS?

Ask disease-specific questions. For example:

• Tinnitus or hearing loss could point to a vestibular disorder.
• Metabolic and cardiovascular disorders such as diabetes, ischemic heart disease, postural hypotension, and seizures can result in presyncope.
• Orthostasis, coronary ischemic events, hypoglycemia, and transient ischemic attacks may cause dizziness.

5. IS DIZZINESS RECURRENT?

Panic disorder, anxiety disorders, phobia, and psychogenic hyperventilation are commonly associated with chronic, recurrent dizziness episodes.

6. WHAT MEDICATIONS IS THE PATIENT TAKING?

All psychotropics are suspect when a patient presents with dizziness. When dizziness occurs after a dose or start of therapy, evaluate response to the medication and consider reducing the dosage or changing the medication. If symptoms persist, refer the patient back to the primary care physician to investigate for other causes of dizziness.

Psychotropics that may cause dizziness are listed in Table 2, For a list of other medications associated with dizziness, see this article at www.currentpsychiatry.com.

If the above strategies do not reveal a physical cause of dizziness despite multiple physical complaints, consider examining the patient for depression, anxiety, or panic disorder.

Treating a psychiatric cause

If dizziness is found to be psychogenic and the symptoms impede daily activities or contribute to functional decline, treat the psychiatric disorder but carefully weigh the risks and benefits of drug treatment.

Although SSRIs may cause dizziness, these agents are recommended first-line treatment for depression, anxiety, and/or phobia in older patients with dizziness because of their relative lack of anticholinergic action and side effects compared with other antidepressants or anxiolytics.

Coexisting medical symptoms may dictate choice of agent. For example, consider a sedating SSRI for a patient with sleep disturbances caused by dizziness or the psychiatric disorder; choose a nonsedating SSRI if the patient is sleeping normally.

Because SSRIs may cause weight loss, avoid giving them to patients with weight loss associated with dizziness or an underlying psychiatric illness. Mirtazapine, which is associated with weight gain, may offset weight loss. Start mirtazapine at 15 mg at bedtime for older patients.

Start low and go slow when prescribing an SSRI to an older patient. Dosing strategies applicable to younger patients should not be extrapolated to older patients, especially those with dizziness.

We have found that older patients respond well to minimum or below-normal SSRI dosages (Table 3). Titrate very slowly and instruct patients to report dizziness. Reduce the dosage if dizziness emerges.

If the patient does not respond to an SSRI or mirtazapine, consider a serotonin and norepinephrine reuptake inhibitor, which also has favorable anticholinergic and side-effect profiles.

Related resources

• WebMD Health—Dizziness: lightheadedness and vertigo. http://my.webMD.com/hw/health_guide_atoz/hw88500.asp.
• Sloane PD. Clinical research and geriatric dizziness: The blind men and the elephant. J Am Geriatr Soc 1999;47:113-14.
• Kroenke K, Hoffman RM, Einstadter D. How common are various forms of dizziness? A critical review. South Med J 2000;93:160-7.

Drug brand names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Chlordiazepoxide • Librium
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clonazepam • Klonopin
• Diazepam • Valium
• Divalproex/valproic acid • Depakote
• Escitalopram • Lexapro
• Estazolam • ProSom
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Flurazepam • Dalmane
• Gabapentin • Neurontin
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Memantine • Namenda
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenelzine • Nardil
• Phenytoin • Dilantin
• Prochlorperazine • Compazine
• Quazepam • Doral
• Rivastigmine • Exelon
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Tacrine • Cognex
• Temazepam • Restoril
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Triazolam • Halcion
• Trifluoperazine • Vesprin
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosure

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

Acknowledgment

The authors thank Robert Cluxton, PharmD, University of Cincinnati College of Pharmacy, for helping to prepare this manuscript for publication.

Dizziness is common among patients age 65 and older, and more than one-third have a psychiatric disorder that is caused by or is causing their dizziness.¹

When older patients present with dizziness, psychiatrists may be asked to alleviate the psychological symptoms and help identify the underlying disease state.²

More than 60 medical and psychiatric disorders and many medications can cause dizziness. To help you sort through the possibilities, we offer:

• six diagnostic questions to rule out underlying medical problems
• lists of commonly used psychotropics and other drugs that may cause dizziness
• advice on treating depression, anxiety, and panic disorder in an older patient with dizziness while avoiding side effects and drug interactions.

Table 1

Four types of dizziness and their usual causes

Many causes of dizziness

The term “dizziness” is hard to define because of its nonspecific and variable symptom description, multiple causes, and lack of clear diagnostic and management guidelines. In clinical use, dizziness encompasses abnormal sensations relating to perception of the body’s relationship to space.

Some researchers believe dizziness is a distinct geriatric syndrome because numerous factors related to aging cause dizziness,² including physiologic changes (presbystasis), accumulated impairment, disease states, and interactions between multiple medications.

Anxiety, somatization, panic disorder, and depression cause dizziness in the elderly, as do:

• peripheral vestibular disorders
• brainstem cerebrovascular accident
• diabetes mellitus
• neurologic disorders such as Parkinson’s disease
• and cardiovascular disorders.

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants also have been shown to cause dizziness, as have numerous nonpsychotropic agents.

Recognizing patterns, testing hypotheses, and extending the diagnostic process over time can help you differentiate psychogenic from medicationinduced or neurologic dizziness.³ Because the presentation is so complex and the differential diagnosis so broad, algorithmic diagnosis is less effective than a flexible clinical approach that allows for uncertainty in evaluating initial symptoms.

Determining the cause

A thorough patient history and physical examination can uncover a cause of dizziness in 75% of cases.⁴ Look for duration of dizziness symptoms; history of heart disease, diabetes or other illnesses; family history of psychiatric disorders; and other illnesses among family members.

Ask the following six complaint-specific questions to help you narrow the differential diagnosis and rule out nonpsychiatric causes.⁵

1. WHAT TYPE OF DIZZINESS DOES THE PATIENT HAVE?

Four categories—vertigo, presyncope, disequilibrium, and lightheadedness—are used to classify dizziness (Table 1).⁶

Vertigo is a sense that the body or environment is Patients may feel as if the floor is tilting, sinking, rising or veering sideways, or they may feel pulled to one side.

Vertigo is commonly caused by peripheral vestibular disorders—including benign positional vertigo, Meniere’s disease, labyrinthitis, and vestibular neuronitis—and central vestibular disorders associated with cerebrovascular disease, tumors, demyelinating diseases, migraines, seizures, multiple sclerosis and other CNS diseases. Acute-onset vertigo and neurologic signs suggest brainstem infarction.

Nystagmus is usually present, horizontal, and may be rotational at times. A vertical-beating nystagmus points to a probable CNS cause and requires urgent neuroimaging and referral to a neurologist or otolaryngologist.

Presyncope describes near-fainting. A dimming of vision and roaring in the ears may precede presyncope.

Depending on its cause, presyncope may occur regardless of position or only when upright. Common causes include orthostatic hypotension, neurocardiogenic syncope, organic heart disease, arrhythmias, carotid sinus disease, seizures, hypoglycemia, and transient ischemic attacks.

Abrupt presyncopal attacks that occur regardless of position suggest a cardiovascular cause. If onset is gradual and not improved by lying down, suspect a cerebral metabolic cause such as hypoglycemia.

Syncope, like presyncope, often is traced to an underlying cardiovascular disease. Dizziness and syncope often coexist, and both can be multifactorial. Dizziness may precede or follow syncopal episodes.

Differentiating syncope and dizziness is important because many underlying causes of syncope can be fatal. By contrast, dizziness symptoms are usually benign and self-limiting.⁷

A thorough history is critical to distinguishing dizziness from presyncope. Assess medication effects—especially CNS-acting medications, cardiovascular drugs, antihypertensives, antibiotics, and over-the-counter medications such as dextromethorphan and acetaminophen compounds. Also check for dehydration.

Disequilibrium disorder signifies unsteadiness or a loss of balance primarily involving the lower extremities. Symptoms are evoked by walking or standing and relieved by sitting or lying down. Gait is abnormal and balance is compromised without abnormal head sensations.

Common causes include balance and gait disorders, sensorimotor dysfunction, presbystasis, neurodegenerative CNS disorders, and mixed ischemic and degenerative CNS diseases.

Vague lightheadedness is often associated with somatic symptoms such as headache. Some patients describe a floating sensation.

Lightheadedness is frequently associated with anxiety, panic disorder, depression, and somatization. Hyperventilation and agoraphobia are other common causes.

Multiple symptoms, multiple types. Classifying an older patient’s dizziness can be challenging because many patients report symptoms that suggest two or more subtypes.² Also, patients often have trouble describing their dizziness symptoms, sometimes using terms such as “giddiness,” “wooziness,” or “confusion.”

To help patients explain dizziness symptoms more accurately, ask specific questions such as:

• Do you at times feel like you’re about to faint?
• Do you feel as if the room is moving?
• Do you sometimes feel as though you’re going to fall?

Table 2

Psychotropics that may cause dizziness

2. HOW DO DIZZINESS SYMPTOMS RELATE TO POSITION OR MOTION?

By reproducing dizziness symptoms, some quick-maneuver tests can help patients describe their symptoms and may reveal a medical cause.

Dix-Hallpike maneuver.³ Move the patient rapidly from a seated to prone position with the head below the horizontal plane and turned 45 degrees for 10 seconds; then have the patient sit up. Repeat with the head turned to the other side. If dizziness does not occur within a few seconds after each test, rule out benign positional vertigo.

Seated head turn, or head-thrust test, measures qualitative vestibular function.⁸ Move the head rapidly by 45 degrees in a brief, small-amplitude thrust to one side while the patient focuses on your nose; this gauges vestibularocular control. Repeat the test in the other direction. A refixation corrective saccade, occurring as the patient tries to fixate on the target, indicates a possible vestibular disorder.

‘Get-Up and Go’ test, which takes less than 10 seconds, measures balance in older patents.⁹ Have the patient stand up, walk 10 feet, turn around, walk back, and sit down. Watch for staggering, unsteadiness, and use of hands to balance. Onset of symptoms suggests dizziness brought on during activities of daily living and provides information on how dizziness is affecting the patient’s ability to function.

Romberg test. Have the patient stand with heels together, first with eyes open and then closed. Vision and proprioceptive signals are used to compensate for vestibular loss. Thus, a balance disturbance with eyes closed suggests vestibular or spinal proprioceptive problems and may predict risk of falls caused by inability to compensate.⁸

3. WHAT IS THE COURSE OF DIZZINESS?

Differentiating acute, sudden-onset dizziness from chronic, gradual-onset dizziness can help uncover the problem’s cause and seriousness. The latter often has a psychological cause or may point to vestibular or minor cardiovascular problems. Tinetti et al² identified anxiety or depressive symptoms as risk factors among community-based older persons who reported dizziness episodes lasting 1 month.

Table 3

Recommended SSRI starting dosages for older patients

An acute presentation can suggest a panic disorder or acute anxiety state, but first rule out serious conditions such as acute myocardial infarction, arrhythmias, acute infections, GI bleeding, and carbon monoxide poisoning.

Also ask about:

• exacerbating and relieving factors. For example, positional changes, exercise or other physical activity, eating, or missing a meal can trigger presyncope. Also find out about situations that may bring on anxiety, panic, or phobia. Onset of dizziness following these situations may suggest psychogenesis.
• recent falls and injuries. Recurrent falls with presyncope suggest a probable orthostatic or cardiovascular diagnosis in older adults.

4. ANY PAST MEDICAL PROBLEMS?

Ask disease-specific questions. For example:

• Tinnitus or hearing loss could point to a vestibular disorder.
• Metabolic and cardiovascular disorders such as diabetes, ischemic heart disease, postural hypotension, and seizures can result in presyncope.
• Orthostasis, coronary ischemic events, hypoglycemia, and transient ischemic attacks may cause dizziness.

5. IS DIZZINESS RECURRENT?

Panic disorder, anxiety disorders, phobia, and psychogenic hyperventilation are commonly associated with chronic, recurrent dizziness episodes.

6. WHAT MEDICATIONS IS THE PATIENT TAKING?

All psychotropics are suspect when a patient presents with dizziness. When dizziness occurs after a dose or start of therapy, evaluate response to the medication and consider reducing the dosage or changing the medication. If symptoms persist, refer the patient back to the primary care physician to investigate for other causes of dizziness.

Psychotropics that may cause dizziness are listed in Table 2, For a list of other medications associated with dizziness, see this article at www.currentpsychiatry.com.

If the above strategies do not reveal a physical cause of dizziness despite multiple physical complaints, consider examining the patient for depression, anxiety, or panic disorder.

Treating a psychiatric cause

If dizziness is found to be psychogenic and the symptoms impede daily activities or contribute to functional decline, treat the psychiatric disorder but carefully weigh the risks and benefits of drug treatment.

Although SSRIs may cause dizziness, these agents are recommended first-line treatment for depression, anxiety, and/or phobia in older patients with dizziness because of their relative lack of anticholinergic action and side effects compared with other antidepressants or anxiolytics.

Coexisting medical symptoms may dictate choice of agent. For example, consider a sedating SSRI for a patient with sleep disturbances caused by dizziness or the psychiatric disorder; choose a nonsedating SSRI if the patient is sleeping normally.

Because SSRIs may cause weight loss, avoid giving them to patients with weight loss associated with dizziness or an underlying psychiatric illness. Mirtazapine, which is associated with weight gain, may offset weight loss. Start mirtazapine at 15 mg at bedtime for older patients.

Start low and go slow when prescribing an SSRI to an older patient. Dosing strategies applicable to younger patients should not be extrapolated to older patients, especially those with dizziness.

We have found that older patients respond well to minimum or below-normal SSRI dosages (Table 3). Titrate very slowly and instruct patients to report dizziness. Reduce the dosage if dizziness emerges.

If the patient does not respond to an SSRI or mirtazapine, consider a serotonin and norepinephrine reuptake inhibitor, which also has favorable anticholinergic and side-effect profiles.

Related resources

• WebMD Health—Dizziness: lightheadedness and vertigo. http://my.webMD.com/hw/health_guide_atoz/hw88500.asp.
• Sloane PD. Clinical research and geriatric dizziness: The blind men and the elephant. J Am Geriatr Soc 1999;47:113-14.
• Kroenke K, Hoffman RM, Einstadter D. How common are various forms of dizziness? A critical review. South Med J 2000;93:160-7.

Drug brand names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol
• Chlordiazepoxide • Librium
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clonazepam • Klonopin
• Diazepam • Valium
• Divalproex/valproic acid • Depakote
• Escitalopram • Lexapro
• Estazolam • ProSom
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Flurazepam • Dalmane
• Gabapentin • Neurontin
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Memantine • Namenda
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Oxcarbazepine • Trileptal
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenelzine • Nardil
• Phenytoin • Dilantin
• Prochlorperazine • Compazine
• Quazepam • Doral
• Rivastigmine • Exelon
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Tacrine • Cognex
• Temazepam • Restoril
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Triazolam • Halcion
• Trifluoperazine • Vesprin
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosure

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

Acknowledgment

The authors thank Robert Cluxton, PharmD, University of Cincinnati College of Pharmacy, for helping to prepare this manuscript for publication.

Just three words—“My tummy hurts”—can mobilize a child’s parents into a high state of worry, especially on school days. They wonder: Is our child sick? Should he or she stay home? Why is this happening so often?

Although recurrent abdominal pain (RAP) is real, it usually is not caused by tissue damage or serious physical disease. When children with RAP are referred for psychiatric evaluation—often after extensive medical workups—we can help them and their parents manage the problem and function more normally. This article:

• describes physiologic mechanisms that may underlie recurrent GI distress
• discusses the high correlation of psychiatric comorbidities with RAP
• recommends judicious laboratory testing
• reviews evidence on medications and psychotherapies to improve RAP symptoms
• offers advice on building a therapeutic alliance with the patient and family.

Figure Comorbid anxiety and depressive disorders in children with RAP

Children with functional RAP are much more likely to be anxious or depressed than similar pain-free children. A recent blinded study followed 80 children ages 8 to 15 (42 with RAP and 38 controls) identified through screening at primary care pediatric offices. Each was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version (K-SADS-PL). Percentage meeting diagnostic criteria

Source: Reference 5.

RAP: A ‘Functional’ disorder

RAP is a somatoform (or “functional”) disorder, defined as physical symptoms not fully explained by a medical condition, effects of a substance, or another mental disorder. Symptoms cause distress and/or functional impairment and are not intentionally produced.¹

A patient with RAP experiences at least three episodes of abdominal pain over 3 months that interfere with daily activities.² RAP affects 7% to 25% of school-aged children and adolescents,³ most of whom have a functional disorder.⁴

RAP is equally common among prepubertal boys and girls but more common among girls during adolescence.³ RAP can impair school attendance and performance and stigmatize a child as “sickly.”

Common comorbid symptoms

Physical. Besides stomach pain, children with RAP often experience headaches (including migraines), other GI symptoms, general aches and pains, dizziness, and fatigue.

Patients with RAP who do not experience GI bleeding, anemia, fever, weight loss, growth failure, or persistent vomiting most likely do not have a serious underlying disease.

Psychiatric. Children with RAP have much higher rates of anxiety (80%) and depressive (40%) disorders than do their unaffected peers (Figure).⁵ We have also seen higher levels of suicidal thinking in children with RAP in primary care settings compared with pain-free controls (14% vs. 4%, P = 0.04; unpublished data).

In most cases, psychiatric comorbidities appear to precede or coincide with RAP onset. Separation fears, generalized anxiety, and social anxiety in particular are common in patients with RAP yet are seldom recognized in medical settings.

Having childhood RAP increases the risk of anxiety, depression, and hypochondriacal fears in adulthood.⁶ We do not know whether early intervention prevents later disability.

Use of medical services. Abdominal pain accounts for 2% to 4% of all pediatric office visits.⁷ In one study, 8% of middle school and high school students said they had visited a physician for evaluation of stomach pain during the previous year.⁸ Children with RAP make more ambulatory health and mental health visits than peers⁹ and are at risk for unnecessary and potentially dangerous medical tests, procedures, and treatments, including abdominal surgery.¹⁰

Four functional GI disorders

To better characterize youths with functional RAP, symptom-based criteria have been developed and applied for functional GI disorders, defined as chronic or recurrent GI symptoms without explanatory structural or biochemical abnormalities.¹¹ Four such disorders are relevant in children with RAP.

Irritable bowel syndrome (IBS): RAP with at least two of the following symptoms: relief with defecation, change in stool frequency, and change in stool form or appearance (occurs in approximately 50% of RAP cases).

Functional dyspepsia: RAP centered in the upper abdomen that is not associated with changes in bowel habits.

Abdominal migraine: Paroxysmal midline abdominal pain lasting 2 hours to several days with symptom-free intervals of weeks to months and at least two of the following: headache during episodes, photophobia during episodes, unilateral headache, aura, and a family history of migraine.

Functional abdominal pain: Continuous or nearly continuous abdominal pain for 6 months or more.

The reliability, validity, and clinical relevance of these criteria have not been demonstrated. Some children with RAP do not meet any criteria for a specific functional GI disorder.

Gut-brain connections. RAP may be associated with a heightened sensitivity to visceral sensations (visceral hyperalgesia) and a low pressure-pain threshold, leading to speculation that these children are hypersensitive to pain.

High rates of anxiety disorders and temperamental harm avoidance also are seen in patients with RAP, along with a tendency to develop pain when faced with unexpected events. Whether these children are more likely than others to perceive novel internal or external perceptions as threatening is open to debate.

Table 1

Recurrent abdominal pain: 8 steps to assessment and diagnosis

Serotonin communicates nociceptive information between the gut and brain and may mediate visceral hyperalgesia. Gut enterochromaffin cells contain more than 90% of the body’s total serotonin. They act as sensory transducers, releasing serotonin in response to increased intraluminal pressure or inflammation.

The released serotonin can cause abdominal discomfort by stimulating 5-HT 3 receptors on vagal afferents and can influence gut peristaltic activity by stimulating enteric afferents. The same serotonin transporter responsible for CNS serotonin reuptake is expressed throughout the gut.

A constellation of clues

The ideal RAP evaluation includes information from the child, parents, educators, and other health care professionals (Table 1).

Begin by acknowledging the patient’s suffering and the parent’s concerns; do not challenge the pain’s subjective reality. Rather than prejudging its cause, document the pain’s timing, context, and characteristics, and review the patient’s history. A constellation of clues is most suggestive of RAP (Table 2); single clues are not definitive.^12,13

Table 2

Clues that suggest functional pain*

Diagnostic testing. Be judicious in selecting diagnostic tests and procedures. Continuing to order studies in a haphazard effort to rule out disease can generate concerns that “the doctor doesn’t know what’s wrong” and heighten the family’s fear that a disease has been missed.

The process of “ruling out” physical disease may have no apparent end. Unless you are reasonably comfortable that a serious physical disease has not been missed, it is difficult to explain RAP to the patient and family and lay the foundation for intervention.

On the other hand, you must balance the importance of minimizing your own and the family’s anxiety about unrecognized disease against the physical and psychological risks and costs associated with medical tests and procedures.

Social assessment. Assess social and familial reinforcement (secondary gain) of the pain. Parents sometimes inadvertently encourage their children’s sick-role behaviors by providing excessive attention, rewards, or opportunities to avoid uncomfortable situations. RAP can become an excuse for poor performance (self-handicapping), particularly in children with a learning disorder.

How to deliver the diagnosis

Functional abdominal pain is essentially a clinical diagnosis that relies on presentation, course, and findings. As mentioned, a constellation of “clues” is most supportive, as is having typical IBS symptoms.

Before declaring the diagnosis, discuss with the family the patient’s physical, emotional, and behavioral symptoms and the context in which RAP developed. Doing so can help maintain your credibility and establish a consensus.

Once you declare the diagnosis, discuss it clearly and frankly. Families are not likely to be reassured if you do not offer a plausible explanation for the lack of physical findings.

Precautions. When a definitive diagnosis is not possible, acknowledge that uncertainty. Although you must discuss any recognized psychiatric comorbidity, attempting to “explain” that the disorder is causing the pain is usually impractical and intellectually dishonest.

Also, given the pervasive nature of stigma, do not convey embarrassment or unease about diagnosing functional RAP or any comorbid psychiatric disorder.

Follow-up testing. Once you diagnose functional RAP, further testing is generally not necessary. Tests might be indicated if you:

• receive new information
• observe a change in clinical status
• or are convinced that treatment will not work unless the family is reassured by further investigation.

Collaborative treatment

Reassurance and education. Reassurance that the patient does not have a serious physical disease is necessary but rarely sufficient. Explain that the child’s pain does not appear to reflect tissue damage and is not threatening. On the other hand, avoid giving excessive reassurance, particularly when obsessional illness worry and hypochondriacal fears are prominent. Address illness worry as a problem to be solved together.

Discuss with the patient and family what is known and not known about functional RAP, and encourage them to ask questions. This is an opportunity for you to instill hope and cultivate positive expectations, but avoid promising cure. Discuss the gut-brain connection and relevance of visceral hyperalgesia, including serotonin’s potential roles in RAP pathogenesis.

Partners in care. Collaborative treatment increases the likelihood of success. Discuss the importance of a therapeutic partnership, and clarify any areas of disagreement with the diagnosis or treatment plan.

Clearly delineate your roles and responsibilities and those of the patient, family, and other health care team members. Poor communication is pediatricians’ most common complaint about psychiatrists.¹⁴ Good interdisciplinary communication decreases the chance that treatment strategies will be duplicated, diluted, or misinterpreted.

Consolidate medical care with a single clinician—often the primary care physician—based on discussions with the patient, family, and health care team. The coordinating clinician can mediate between the school and family when tensions develop over poor attendance or requests for special treatment. It is often useful for this clinician to spell out:

• what constitutes a legitimate medical excuse for school absence
• who will legitimize excuses.

All parties should understand that the school will view an unexcused absence as truancy and act appropriately.

Diet and lifestyle. Encourage the patient to maintain a regular schedule and a healthy diet. Specific dietary interventions have not been proven effective, despite speculation that lack of dietary fiber or lactose intolerance might cause RAP.^15,16 Also encourage adequate sleep and regular exercise.

Medication and psychotherapy

Because no strong evidence-based guidelines address pediatric RAP intervention, family preferences usually guide initial treatment decisions. This highlights the importance of good communication and a therapeutic partnership among the clinician, family, and patient.

Antispasmodics, acid reducers, and antidepressants are commonly prescribed for RAP, though none are well-supported in the literature and no controlled studies have gauged medication’s impact on psychiatric comorbidity.¹⁶

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) might help relieve RAP symptoms, but the evidence is inconclusive. SSRIs are considered potentially beneficial in RAP because they may help communicate nociceptive information between the gut and brain and mediate visceral hyperalgesia.

SSRIs at first may increase serotonin at the synapse, which one might assume would to worsen abdominal symptoms. However, ongoing SSRI use could “down-regulate” postsynaptic 5-HT₃ receptors and desensitize postsynaptic cells to the effects of local serotonin.

Our group recently conducted a 12-week open trial of citalopram for functional pediatric RAP.¹⁷ The 25 participants received 10 mg/d the first week, then 20 mg/d thereafter if tolerated. At week 4, nonresponders and partial responders who were tolerating the medication began receiving 40 mg/d.

Table 3

SSRI daily dosing for pediatric RAP

At trial’s end, more than two-thirds of participants were taking 40 mg/d. We rated 21 of 25 patients (84%) as “much improved” or “very much improved,” using the Clinical Global Impression-Improvement scale. Abdominal pain, anxiety, depression, other somatic symptoms, and functional impairment all improved significantly during treatment. Suicidal thoughts diminished progressively from baseline, and no patient reported suicidal thinking at study’s end. Citalopram was generally well tolerated.

With SSRI treatment, start at a low dosage for 3 to 7 days (Table 3). If tolerated, increase to a typical therapeutic dosage. If symptoms fail to respond after 2 or 3 weeks, consider a higher dosage. A short course of an oral benzodiazepine (such as clonazepam, 0.25 mg bid) during the first weeks of SSRI treatment sometimes helps particularly anxious patients or those whose pain appears closely associated with anxiety or “stress.”

Pediatric gastroenterologists often prescribe a low-dose tricyclic antidepressant as first-line therapy, but we discourage this. TCAs lack efficacy in pediatric depression and pose a greater risk of side effects and safety concerns than SSRIs.¹⁸

Other agents have been tried for RAP-associated conditions:

Famotidine, a histamine type 2 receptor blocker, may reduce pain in children with dyspepsia and RAP.¹⁹

Peppermint oil reduced abdominal pain in one study of children with IBS but had little effect on other symptoms.²⁰

Medications such as alosetron and tegaserod that interrupt serotonergic neurotransmission in the gut have shown benefit in adults with IBS but have not been studied in children.

Psychotherapy. A few small studies suggest that cognitive-behavioral therapies (CBT) are helpful in RAP, but CBT may be difficult to deliver in medical settings.^21,22 A simplified “rehabilitative” approach that incorporates CBT principles involves having the clinician and patient view RAP as a challenge to be overcome, rather than a burden to be endured. Such an approach emphasizes the child’s fundamental strength and adaptability rather than vulnerabilities.

The goal of therapy is redirected from finding a cure to coping with and overcoming the problem. This approach challenges the notion that the child cannot resume normal function until the pain is completely gone. It encourages active, problem-focused coping, and discourages passive acceptance—which is associated with greater symptom burden and functional impairment.

Work with parents to reinforce the child’s health-promoting behaviors and minimize negative and social reinforcements (secondary gain) associated with RAP. Advise parents to:

• encourage and reward full school attendance
• avoid home-bound instruction
• expect the child to function despite physical distress
• insist that the child perform age-appropriate household chores and other responsibilities.

Self-management skills—such as relaxation training, hypnosis, biofeedback, and guided imagery—may help reduce pain and manage physiologic arousal.¹⁶ Deception strategies such as placebo or sham interventions are unethical and impractical.

Related resources

• Campo JV. Functional recurrent abdominal pain in children and adolescents. Digestive Health Matters 2003;12(3):15-7.
• International Foundation for Functional Gastrointestinal Disorders. www.iffgd.org
• University of Pittsburgh. Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders. www.moodykids.org

Drug brand names

• Alosetron • Lotronex
• Citalopram • Celexa
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Sertraline • Zoloft
• Tegaserod • Zelnorm

Disclosure

Dr. Campo’s work has been supported by the National Institute of Mental Health (grant MH01780) and in part by the Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders (grant MH66371). He also receives grants from Forest Pharmaceuticals and is a consultant to Eli Lilly and Co.

Just three words—“My tummy hurts”—can mobilize a child’s parents into a high state of worry, especially on school days. They wonder: Is our child sick? Should he or she stay home? Why is this happening so often?

Although recurrent abdominal pain (RAP) is real, it usually is not caused by tissue damage or serious physical disease. When children with RAP are referred for psychiatric evaluation—often after extensive medical workups—we can help them and their parents manage the problem and function more normally. This article:

• describes physiologic mechanisms that may underlie recurrent GI distress
• discusses the high correlation of psychiatric comorbidities with RAP
• recommends judicious laboratory testing
• reviews evidence on medications and psychotherapies to improve RAP symptoms
• offers advice on building a therapeutic alliance with the patient and family.

Figure Comorbid anxiety and depressive disorders in children with RAP

Children with functional RAP are much more likely to be anxious or depressed than similar pain-free children. A recent blinded study followed 80 children ages 8 to 15 (42 with RAP and 38 controls) identified through screening at primary care pediatric offices. Each was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version (K-SADS-PL). Percentage meeting diagnostic criteria

Source: Reference 5.

RAP: A ‘Functional’ disorder

RAP is a somatoform (or “functional”) disorder, defined as physical symptoms not fully explained by a medical condition, effects of a substance, or another mental disorder. Symptoms cause distress and/or functional impairment and are not intentionally produced.¹

A patient with RAP experiences at least three episodes of abdominal pain over 3 months that interfere with daily activities.² RAP affects 7% to 25% of school-aged children and adolescents,³ most of whom have a functional disorder.⁴

RAP is equally common among prepubertal boys and girls but more common among girls during adolescence.³ RAP can impair school attendance and performance and stigmatize a child as “sickly.”

Common comorbid symptoms

Physical. Besides stomach pain, children with RAP often experience headaches (including migraines), other GI symptoms, general aches and pains, dizziness, and fatigue.

Patients with RAP who do not experience GI bleeding, anemia, fever, weight loss, growth failure, or persistent vomiting most likely do not have a serious underlying disease.

Psychiatric. Children with RAP have much higher rates of anxiety (80%) and depressive (40%) disorders than do their unaffected peers (Figure).⁵ We have also seen higher levels of suicidal thinking in children with RAP in primary care settings compared with pain-free controls (14% vs. 4%, P = 0.04; unpublished data).

In most cases, psychiatric comorbidities appear to precede or coincide with RAP onset. Separation fears, generalized anxiety, and social anxiety in particular are common in patients with RAP yet are seldom recognized in medical settings.

Having childhood RAP increases the risk of anxiety, depression, and hypochondriacal fears in adulthood.⁶ We do not know whether early intervention prevents later disability.

Use of medical services. Abdominal pain accounts for 2% to 4% of all pediatric office visits.⁷ In one study, 8% of middle school and high school students said they had visited a physician for evaluation of stomach pain during the previous year.⁸ Children with RAP make more ambulatory health and mental health visits than peers⁹ and are at risk for unnecessary and potentially dangerous medical tests, procedures, and treatments, including abdominal surgery.¹⁰

Four functional GI disorders

To better characterize youths with functional RAP, symptom-based criteria have been developed and applied for functional GI disorders, defined as chronic or recurrent GI symptoms without explanatory structural or biochemical abnormalities.¹¹ Four such disorders are relevant in children with RAP.

Irritable bowel syndrome (IBS): RAP with at least two of the following symptoms: relief with defecation, change in stool frequency, and change in stool form or appearance (occurs in approximately 50% of RAP cases).

Functional dyspepsia: RAP centered in the upper abdomen that is not associated with changes in bowel habits.

Abdominal migraine: Paroxysmal midline abdominal pain lasting 2 hours to several days with symptom-free intervals of weeks to months and at least two of the following: headache during episodes, photophobia during episodes, unilateral headache, aura, and a family history of migraine.

Functional abdominal pain: Continuous or nearly continuous abdominal pain for 6 months or more.

The reliability, validity, and clinical relevance of these criteria have not been demonstrated. Some children with RAP do not meet any criteria for a specific functional GI disorder.

Gut-brain connections. RAP may be associated with a heightened sensitivity to visceral sensations (visceral hyperalgesia) and a low pressure-pain threshold, leading to speculation that these children are hypersensitive to pain.

High rates of anxiety disorders and temperamental harm avoidance also are seen in patients with RAP, along with a tendency to develop pain when faced with unexpected events. Whether these children are more likely than others to perceive novel internal or external perceptions as threatening is open to debate.

Table 1

Recurrent abdominal pain: 8 steps to assessment and diagnosis

Serotonin communicates nociceptive information between the gut and brain and may mediate visceral hyperalgesia. Gut enterochromaffin cells contain more than 90% of the body’s total serotonin. They act as sensory transducers, releasing serotonin in response to increased intraluminal pressure or inflammation.

The released serotonin can cause abdominal discomfort by stimulating 5-HT 3 receptors on vagal afferents and can influence gut peristaltic activity by stimulating enteric afferents. The same serotonin transporter responsible for CNS serotonin reuptake is expressed throughout the gut.

A constellation of clues

The ideal RAP evaluation includes information from the child, parents, educators, and other health care professionals (Table 1).

Begin by acknowledging the patient’s suffering and the parent’s concerns; do not challenge the pain’s subjective reality. Rather than prejudging its cause, document the pain’s timing, context, and characteristics, and review the patient’s history. A constellation of clues is most suggestive of RAP (Table 2); single clues are not definitive.^12,13

Table 2

Clues that suggest functional pain*

Diagnostic testing. Be judicious in selecting diagnostic tests and procedures. Continuing to order studies in a haphazard effort to rule out disease can generate concerns that “the doctor doesn’t know what’s wrong” and heighten the family’s fear that a disease has been missed.

The process of “ruling out” physical disease may have no apparent end. Unless you are reasonably comfortable that a serious physical disease has not been missed, it is difficult to explain RAP to the patient and family and lay the foundation for intervention.

On the other hand, you must balance the importance of minimizing your own and the family’s anxiety about unrecognized disease against the physical and psychological risks and costs associated with medical tests and procedures.

Social assessment. Assess social and familial reinforcement (secondary gain) of the pain. Parents sometimes inadvertently encourage their children’s sick-role behaviors by providing excessive attention, rewards, or opportunities to avoid uncomfortable situations. RAP can become an excuse for poor performance (self-handicapping), particularly in children with a learning disorder.

How to deliver the diagnosis

Functional abdominal pain is essentially a clinical diagnosis that relies on presentation, course, and findings. As mentioned, a constellation of “clues” is most supportive, as is having typical IBS symptoms.

Before declaring the diagnosis, discuss with the family the patient’s physical, emotional, and behavioral symptoms and the context in which RAP developed. Doing so can help maintain your credibility and establish a consensus.

Once you declare the diagnosis, discuss it clearly and frankly. Families are not likely to be reassured if you do not offer a plausible explanation for the lack of physical findings.

Precautions. When a definitive diagnosis is not possible, acknowledge that uncertainty. Although you must discuss any recognized psychiatric comorbidity, attempting to “explain” that the disorder is causing the pain is usually impractical and intellectually dishonest.

Also, given the pervasive nature of stigma, do not convey embarrassment or unease about diagnosing functional RAP or any comorbid psychiatric disorder.

Follow-up testing. Once you diagnose functional RAP, further testing is generally not necessary. Tests might be indicated if you:

• receive new information
• observe a change in clinical status
• or are convinced that treatment will not work unless the family is reassured by further investigation.

Collaborative treatment

Reassurance and education. Reassurance that the patient does not have a serious physical disease is necessary but rarely sufficient. Explain that the child’s pain does not appear to reflect tissue damage and is not threatening. On the other hand, avoid giving excessive reassurance, particularly when obsessional illness worry and hypochondriacal fears are prominent. Address illness worry as a problem to be solved together.

Discuss with the patient and family what is known and not known about functional RAP, and encourage them to ask questions. This is an opportunity for you to instill hope and cultivate positive expectations, but avoid promising cure. Discuss the gut-brain connection and relevance of visceral hyperalgesia, including serotonin’s potential roles in RAP pathogenesis.

Partners in care. Collaborative treatment increases the likelihood of success. Discuss the importance of a therapeutic partnership, and clarify any areas of disagreement with the diagnosis or treatment plan.

Clearly delineate your roles and responsibilities and those of the patient, family, and other health care team members. Poor communication is pediatricians’ most common complaint about psychiatrists.¹⁴ Good interdisciplinary communication decreases the chance that treatment strategies will be duplicated, diluted, or misinterpreted.

Consolidate medical care with a single clinician—often the primary care physician—based on discussions with the patient, family, and health care team. The coordinating clinician can mediate between the school and family when tensions develop over poor attendance or requests for special treatment. It is often useful for this clinician to spell out:

• what constitutes a legitimate medical excuse for school absence
• who will legitimize excuses.

All parties should understand that the school will view an unexcused absence as truancy and act appropriately.

Diet and lifestyle. Encourage the patient to maintain a regular schedule and a healthy diet. Specific dietary interventions have not been proven effective, despite speculation that lack of dietary fiber or lactose intolerance might cause RAP.^15,16 Also encourage adequate sleep and regular exercise.

Medication and psychotherapy

Because no strong evidence-based guidelines address pediatric RAP intervention, family preferences usually guide initial treatment decisions. This highlights the importance of good communication and a therapeutic partnership among the clinician, family, and patient.

Antispasmodics, acid reducers, and antidepressants are commonly prescribed for RAP, though none are well-supported in the literature and no controlled studies have gauged medication’s impact on psychiatric comorbidity.¹⁶

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) might help relieve RAP symptoms, but the evidence is inconclusive. SSRIs are considered potentially beneficial in RAP because they may help communicate nociceptive information between the gut and brain and mediate visceral hyperalgesia.

SSRIs at first may increase serotonin at the synapse, which one might assume would to worsen abdominal symptoms. However, ongoing SSRI use could “down-regulate” postsynaptic 5-HT₃ receptors and desensitize postsynaptic cells to the effects of local serotonin.

Our group recently conducted a 12-week open trial of citalopram for functional pediatric RAP.¹⁷ The 25 participants received 10 mg/d the first week, then 20 mg/d thereafter if tolerated. At week 4, nonresponders and partial responders who were tolerating the medication began receiving 40 mg/d.

Table 3

SSRI daily dosing for pediatric RAP

At trial’s end, more than two-thirds of participants were taking 40 mg/d. We rated 21 of 25 patients (84%) as “much improved” or “very much improved,” using the Clinical Global Impression-Improvement scale. Abdominal pain, anxiety, depression, other somatic symptoms, and functional impairment all improved significantly during treatment. Suicidal thoughts diminished progressively from baseline, and no patient reported suicidal thinking at study’s end. Citalopram was generally well tolerated.

With SSRI treatment, start at a low dosage for 3 to 7 days (Table 3). If tolerated, increase to a typical therapeutic dosage. If symptoms fail to respond after 2 or 3 weeks, consider a higher dosage. A short course of an oral benzodiazepine (such as clonazepam, 0.25 mg bid) during the first weeks of SSRI treatment sometimes helps particularly anxious patients or those whose pain appears closely associated with anxiety or “stress.”

Pediatric gastroenterologists often prescribe a low-dose tricyclic antidepressant as first-line therapy, but we discourage this. TCAs lack efficacy in pediatric depression and pose a greater risk of side effects and safety concerns than SSRIs.¹⁸

Other agents have been tried for RAP-associated conditions:

Famotidine, a histamine type 2 receptor blocker, may reduce pain in children with dyspepsia and RAP.¹⁹

Peppermint oil reduced abdominal pain in one study of children with IBS but had little effect on other symptoms.²⁰

Medications such as alosetron and tegaserod that interrupt serotonergic neurotransmission in the gut have shown benefit in adults with IBS but have not been studied in children.

Psychotherapy. A few small studies suggest that cognitive-behavioral therapies (CBT) are helpful in RAP, but CBT may be difficult to deliver in medical settings.^21,22 A simplified “rehabilitative” approach that incorporates CBT principles involves having the clinician and patient view RAP as a challenge to be overcome, rather than a burden to be endured. Such an approach emphasizes the child’s fundamental strength and adaptability rather than vulnerabilities.

The goal of therapy is redirected from finding a cure to coping with and overcoming the problem. This approach challenges the notion that the child cannot resume normal function until the pain is completely gone. It encourages active, problem-focused coping, and discourages passive acceptance—which is associated with greater symptom burden and functional impairment.

Work with parents to reinforce the child’s health-promoting behaviors and minimize negative and social reinforcements (secondary gain) associated with RAP. Advise parents to:

• encourage and reward full school attendance
• avoid home-bound instruction
• expect the child to function despite physical distress
• insist that the child perform age-appropriate household chores and other responsibilities.

Self-management skills—such as relaxation training, hypnosis, biofeedback, and guided imagery—may help reduce pain and manage physiologic arousal.¹⁶ Deception strategies such as placebo or sham interventions are unethical and impractical.

Related resources

• Campo JV. Functional recurrent abdominal pain in children and adolescents. Digestive Health Matters 2003;12(3):15-7.
• International Foundation for Functional Gastrointestinal Disorders. www.iffgd.org
• University of Pittsburgh. Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders. www.moodykids.org

Drug brand names

• Alosetron • Lotronex
• Citalopram • Celexa
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Sertraline • Zoloft
• Tegaserod • Zelnorm

Disclosure

Dr. Campo’s work has been supported by the National Institute of Mental Health (grant MH01780) and in part by the Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders (grant MH66371). He also receives grants from Forest Pharmaceuticals and is a consultant to Eli Lilly and Co.

Just three words—“My tummy hurts”—can mobilize a child’s parents into a high state of worry, especially on school days. They wonder: Is our child sick? Should he or she stay home? Why is this happening so often?

Although recurrent abdominal pain (RAP) is real, it usually is not caused by tissue damage or serious physical disease. When children with RAP are referred for psychiatric evaluation—often after extensive medical workups—we can help them and their parents manage the problem and function more normally. This article:

• describes physiologic mechanisms that may underlie recurrent GI distress
• discusses the high correlation of psychiatric comorbidities with RAP
• recommends judicious laboratory testing
• reviews evidence on medications and psychotherapies to improve RAP symptoms
• offers advice on building a therapeutic alliance with the patient and family.

Figure Comorbid anxiety and depressive disorders in children with RAP

Children with functional RAP are much more likely to be anxious or depressed than similar pain-free children. A recent blinded study followed 80 children ages 8 to 15 (42 with RAP and 38 controls) identified through screening at primary care pediatric offices. Each was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version (K-SADS-PL). Percentage meeting diagnostic criteria

Source: Reference 5.

RAP: A ‘Functional’ disorder

RAP is a somatoform (or “functional”) disorder, defined as physical symptoms not fully explained by a medical condition, effects of a substance, or another mental disorder. Symptoms cause distress and/or functional impairment and are not intentionally produced.¹

A patient with RAP experiences at least three episodes of abdominal pain over 3 months that interfere with daily activities.² RAP affects 7% to 25% of school-aged children and adolescents,³ most of whom have a functional disorder.⁴

RAP is equally common among prepubertal boys and girls but more common among girls during adolescence.³ RAP can impair school attendance and performance and stigmatize a child as “sickly.”

Common comorbid symptoms

Physical. Besides stomach pain, children with RAP often experience headaches (including migraines), other GI symptoms, general aches and pains, dizziness, and fatigue.

Patients with RAP who do not experience GI bleeding, anemia, fever, weight loss, growth failure, or persistent vomiting most likely do not have a serious underlying disease.

Psychiatric. Children with RAP have much higher rates of anxiety (80%) and depressive (40%) disorders than do their unaffected peers (Figure).⁵ We have also seen higher levels of suicidal thinking in children with RAP in primary care settings compared with pain-free controls (14% vs. 4%, P = 0.04; unpublished data).

In most cases, psychiatric comorbidities appear to precede or coincide with RAP onset. Separation fears, generalized anxiety, and social anxiety in particular are common in patients with RAP yet are seldom recognized in medical settings.

Having childhood RAP increases the risk of anxiety, depression, and hypochondriacal fears in adulthood.⁶ We do not know whether early intervention prevents later disability.

Use of medical services. Abdominal pain accounts for 2% to 4% of all pediatric office visits.⁷ In one study, 8% of middle school and high school students said they had visited a physician for evaluation of stomach pain during the previous year.⁸ Children with RAP make more ambulatory health and mental health visits than peers⁹ and are at risk for unnecessary and potentially dangerous medical tests, procedures, and treatments, including abdominal surgery.¹⁰

Four functional GI disorders

To better characterize youths with functional RAP, symptom-based criteria have been developed and applied for functional GI disorders, defined as chronic or recurrent GI symptoms without explanatory structural or biochemical abnormalities.¹¹ Four such disorders are relevant in children with RAP.

Irritable bowel syndrome (IBS): RAP with at least two of the following symptoms: relief with defecation, change in stool frequency, and change in stool form or appearance (occurs in approximately 50% of RAP cases).

Functional dyspepsia: RAP centered in the upper abdomen that is not associated with changes in bowel habits.

Abdominal migraine: Paroxysmal midline abdominal pain lasting 2 hours to several days with symptom-free intervals of weeks to months and at least two of the following: headache during episodes, photophobia during episodes, unilateral headache, aura, and a family history of migraine.

Functional abdominal pain: Continuous or nearly continuous abdominal pain for 6 months or more.

The reliability, validity, and clinical relevance of these criteria have not been demonstrated. Some children with RAP do not meet any criteria for a specific functional GI disorder.

Gut-brain connections. RAP may be associated with a heightened sensitivity to visceral sensations (visceral hyperalgesia) and a low pressure-pain threshold, leading to speculation that these children are hypersensitive to pain.

High rates of anxiety disorders and temperamental harm avoidance also are seen in patients with RAP, along with a tendency to develop pain when faced with unexpected events. Whether these children are more likely than others to perceive novel internal or external perceptions as threatening is open to debate.

Table 1

Recurrent abdominal pain: 8 steps to assessment and diagnosis

Serotonin communicates nociceptive information between the gut and brain and may mediate visceral hyperalgesia. Gut enterochromaffin cells contain more than 90% of the body’s total serotonin. They act as sensory transducers, releasing serotonin in response to increased intraluminal pressure or inflammation.

The released serotonin can cause abdominal discomfort by stimulating 5-HT 3 receptors on vagal afferents and can influence gut peristaltic activity by stimulating enteric afferents. The same serotonin transporter responsible for CNS serotonin reuptake is expressed throughout the gut.

A constellation of clues

The ideal RAP evaluation includes information from the child, parents, educators, and other health care professionals (Table 1).

Begin by acknowledging the patient’s suffering and the parent’s concerns; do not challenge the pain’s subjective reality. Rather than prejudging its cause, document the pain’s timing, context, and characteristics, and review the patient’s history. A constellation of clues is most suggestive of RAP (Table 2); single clues are not definitive.^12,13

Table 2

Clues that suggest functional pain*

Diagnostic testing. Be judicious in selecting diagnostic tests and procedures. Continuing to order studies in a haphazard effort to rule out disease can generate concerns that “the doctor doesn’t know what’s wrong” and heighten the family’s fear that a disease has been missed.

The process of “ruling out” physical disease may have no apparent end. Unless you are reasonably comfortable that a serious physical disease has not been missed, it is difficult to explain RAP to the patient and family and lay the foundation for intervention.

On the other hand, you must balance the importance of minimizing your own and the family’s anxiety about unrecognized disease against the physical and psychological risks and costs associated with medical tests and procedures.

Social assessment. Assess social and familial reinforcement (secondary gain) of the pain. Parents sometimes inadvertently encourage their children’s sick-role behaviors by providing excessive attention, rewards, or opportunities to avoid uncomfortable situations. RAP can become an excuse for poor performance (self-handicapping), particularly in children with a learning disorder.

How to deliver the diagnosis

Functional abdominal pain is essentially a clinical diagnosis that relies on presentation, course, and findings. As mentioned, a constellation of “clues” is most supportive, as is having typical IBS symptoms.

Before declaring the diagnosis, discuss with the family the patient’s physical, emotional, and behavioral symptoms and the context in which RAP developed. Doing so can help maintain your credibility and establish a consensus.

Once you declare the diagnosis, discuss it clearly and frankly. Families are not likely to be reassured if you do not offer a plausible explanation for the lack of physical findings.

Precautions. When a definitive diagnosis is not possible, acknowledge that uncertainty. Although you must discuss any recognized psychiatric comorbidity, attempting to “explain” that the disorder is causing the pain is usually impractical and intellectually dishonest.

Also, given the pervasive nature of stigma, do not convey embarrassment or unease about diagnosing functional RAP or any comorbid psychiatric disorder.

Follow-up testing. Once you diagnose functional RAP, further testing is generally not necessary. Tests might be indicated if you:

• receive new information
• observe a change in clinical status
• or are convinced that treatment will not work unless the family is reassured by further investigation.

Collaborative treatment

Reassurance and education. Reassurance that the patient does not have a serious physical disease is necessary but rarely sufficient. Explain that the child’s pain does not appear to reflect tissue damage and is not threatening. On the other hand, avoid giving excessive reassurance, particularly when obsessional illness worry and hypochondriacal fears are prominent. Address illness worry as a problem to be solved together.

Discuss with the patient and family what is known and not known about functional RAP, and encourage them to ask questions. This is an opportunity for you to instill hope and cultivate positive expectations, but avoid promising cure. Discuss the gut-brain connection and relevance of visceral hyperalgesia, including serotonin’s potential roles in RAP pathogenesis.

Partners in care. Collaborative treatment increases the likelihood of success. Discuss the importance of a therapeutic partnership, and clarify any areas of disagreement with the diagnosis or treatment plan.

Clearly delineate your roles and responsibilities and those of the patient, family, and other health care team members. Poor communication is pediatricians’ most common complaint about psychiatrists.¹⁴ Good interdisciplinary communication decreases the chance that treatment strategies will be duplicated, diluted, or misinterpreted.

Consolidate medical care with a single clinician—often the primary care physician—based on discussions with the patient, family, and health care team. The coordinating clinician can mediate between the school and family when tensions develop over poor attendance or requests for special treatment. It is often useful for this clinician to spell out:

• what constitutes a legitimate medical excuse for school absence
• who will legitimize excuses.

All parties should understand that the school will view an unexcused absence as truancy and act appropriately.

Diet and lifestyle. Encourage the patient to maintain a regular schedule and a healthy diet. Specific dietary interventions have not been proven effective, despite speculation that lack of dietary fiber or lactose intolerance might cause RAP.^15,16 Also encourage adequate sleep and regular exercise.

Medication and psychotherapy

Because no strong evidence-based guidelines address pediatric RAP intervention, family preferences usually guide initial treatment decisions. This highlights the importance of good communication and a therapeutic partnership among the clinician, family, and patient.

Antispasmodics, acid reducers, and antidepressants are commonly prescribed for RAP, though none are well-supported in the literature and no controlled studies have gauged medication’s impact on psychiatric comorbidity.¹⁶

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) might help relieve RAP symptoms, but the evidence is inconclusive. SSRIs are considered potentially beneficial in RAP because they may help communicate nociceptive information between the gut and brain and mediate visceral hyperalgesia.

SSRIs at first may increase serotonin at the synapse, which one might assume would to worsen abdominal symptoms. However, ongoing SSRI use could “down-regulate” postsynaptic 5-HT₃ receptors and desensitize postsynaptic cells to the effects of local serotonin.

Our group recently conducted a 12-week open trial of citalopram for functional pediatric RAP.¹⁷ The 25 participants received 10 mg/d the first week, then 20 mg/d thereafter if tolerated. At week 4, nonresponders and partial responders who were tolerating the medication began receiving 40 mg/d.

Table 3

SSRI daily dosing for pediatric RAP

At trial’s end, more than two-thirds of participants were taking 40 mg/d. We rated 21 of 25 patients (84%) as “much improved” or “very much improved,” using the Clinical Global Impression-Improvement scale. Abdominal pain, anxiety, depression, other somatic symptoms, and functional impairment all improved significantly during treatment. Suicidal thoughts diminished progressively from baseline, and no patient reported suicidal thinking at study’s end. Citalopram was generally well tolerated.

With SSRI treatment, start at a low dosage for 3 to 7 days (Table 3). If tolerated, increase to a typical therapeutic dosage. If symptoms fail to respond after 2 or 3 weeks, consider a higher dosage. A short course of an oral benzodiazepine (such as clonazepam, 0.25 mg bid) during the first weeks of SSRI treatment sometimes helps particularly anxious patients or those whose pain appears closely associated with anxiety or “stress.”

Pediatric gastroenterologists often prescribe a low-dose tricyclic antidepressant as first-line therapy, but we discourage this. TCAs lack efficacy in pediatric depression and pose a greater risk of side effects and safety concerns than SSRIs.¹⁸

Other agents have been tried for RAP-associated conditions:

Famotidine, a histamine type 2 receptor blocker, may reduce pain in children with dyspepsia and RAP.¹⁹

Peppermint oil reduced abdominal pain in one study of children with IBS but had little effect on other symptoms.²⁰

Medications such as alosetron and tegaserod that interrupt serotonergic neurotransmission in the gut have shown benefit in adults with IBS but have not been studied in children.

Psychotherapy. A few small studies suggest that cognitive-behavioral therapies (CBT) are helpful in RAP, but CBT may be difficult to deliver in medical settings.^21,22 A simplified “rehabilitative” approach that incorporates CBT principles involves having the clinician and patient view RAP as a challenge to be overcome, rather than a burden to be endured. Such an approach emphasizes the child’s fundamental strength and adaptability rather than vulnerabilities.

The goal of therapy is redirected from finding a cure to coping with and overcoming the problem. This approach challenges the notion that the child cannot resume normal function until the pain is completely gone. It encourages active, problem-focused coping, and discourages passive acceptance—which is associated with greater symptom burden and functional impairment.

Work with parents to reinforce the child’s health-promoting behaviors and minimize negative and social reinforcements (secondary gain) associated with RAP. Advise parents to:

• encourage and reward full school attendance
• avoid home-bound instruction
• expect the child to function despite physical distress
• insist that the child perform age-appropriate household chores and other responsibilities.

Self-management skills—such as relaxation training, hypnosis, biofeedback, and guided imagery—may help reduce pain and manage physiologic arousal.¹⁶ Deception strategies such as placebo or sham interventions are unethical and impractical.

Related resources

• Campo JV. Functional recurrent abdominal pain in children and adolescents. Digestive Health Matters 2003;12(3):15-7.
• International Foundation for Functional Gastrointestinal Disorders. www.iffgd.org
• University of Pittsburgh. Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders. www.moodykids.org

Drug brand names

• Alosetron • Lotronex
• Citalopram • Celexa
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Sertraline • Zoloft
• Tegaserod • Zelnorm

Disclosure

Dr. Campo’s work has been supported by the National Institute of Mental Health (grant MH01780) and in part by the Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders (grant MH66371). He also receives grants from Forest Pharmaceuticals and is a consultant to Eli Lilly and Co.

Ms. A, age 44, fell from a 3-foot stool while reaching for a high kitchen shelf and suffered severe neck flexion. Her initial pain persisted for weeks and then months, resulting in chronic neck pain aggravated by movement.

Over the past year, her doctor has prescribed numerous analgesics and muscle relaxants, including tramadol, hydrocodone, oxycodone, tizanidine, and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatments at a pain clinic have included triggerpoint injections, cervical epidural corticosteroid injection, left-sided cervical medial branch blocks, transcutaneous electrical nerve stimulation, and physical therapy. None provided sustained relief.

During a pain clinic visit, Ms. A wept and said she was tired of living with pain. She acknowledged depression and agreed to psychiatric consultation.

As in Ms. A’s case, physicians often refer patients with chronic pain and affective symptoms for psychiatric evaluation. These patients are often fearful, angry, and suspicious of any suggestion that their physical discomfort has a psychiatric component. They typically believe their pain had a clear onset and therefore should have an end point. Many have experienced unproductive specialty evaluations and failed treatments.

To help you overcome these obstacles when treating patients with chronic pain and depression, we discuss:

• strategies to gain patients’ trust and build a therapeutic alliance
• how to assess their pain, depression, and suicide risk
• the role of psychotherapy in treating chronic pain
• and evidence for choosing effective, nonaddicting medications.

Psychiatric evaluation

Depression and pain are linked psychologically and biochemically, sharing neurotransmitters involved in both nociceptive pathways and mood, especially serotonin and norepinephrine.^1,2 One-third to one-half of patients with chronic pain report comorbid depression,³ and more than one-half of depressed patients presenting to primary care physicians report only somatic symptoms—various pain complaints among the most common.^4,5

Primary care doctors tend to refer chronic pain and depression cases to psychiatrists when:

• patients are preoccupied with medication, have not followed treatment recommendations, or do not respond to treatment as expected
• extensive medical evaluations reveal few or equivocal findings
• somatic complaints are vague and diffuse, or there is marked disparity between pain complaints/disability and objective findings.^6,7

Assessing pain. In the initial assessment, validate the patient’s pain experience by asking about the location, quality, and severity of pain. The visual analogue scale (VAS) is commonly used to measure pain severity. The patient marks a spot on a line from “no pain” to “worst possible pain,” or—on a numbered VAS—from 0 (no pain) to 10 (extreme pain). The least and most severe pain over the preceding month can be ranked as baseline values.⁸

Be sensitive to the patient’s fear that you will attribute the pain to psychosocial issues or imply that “the pain is in your head.” Emphasize that you intend to evaluate the “whole person,” not just the part that hurts. Focus on how the pain affects the patient’s lifestyle—rather than its cause—and explore medication use patterns.

Assessing depression. The word “depression” is emotionally charged for chronic pain patients, who view affective symptoms—if they acknowledge them at all—as secondary to pain. They may strongly resist treatment for anything but pain. One way to defuse this defensiveness is to avoid attributing the pain to stress or depression.

Begin by assessing vegetative symptoms, which overlap in chronic pain and depression. The Beck Depression Inventory-II (Beck-II) may be a useful screening tool in a busy practice; the short form (13 questions) takes about 5 minutes to complete.⁹

Explore cognitive and behavioral symptoms such as concentration, pleasure and interest level, activity, and self-esteem. Review the chronology of pain onset, mood changes, and stressors (proximate, remote, and cumulative).

Seek clues to endogenous factors by asking about past affective episodes, response to antidepressants, and family history of psychopathology. Substances that may induce depression include reserpine, interferon, and antiparkinsonian agents. Screen for potential organic mood disorders, such as depression secondary to hypothyroidism, corticosteroid use, Parkinson’s disease, lupus, HIV infection, or cerebrovascular disease. Where appropriate, obtain collateral information from family or friends.

Assessing suicide risk. Chronic pain patients may be at greater risk of suicide than the general population. Besides pain, other risk factors for suicide—such as major depression, anxiety disorders, alcohol/substance abuse, sleep disturbances, male gender, diminished social support, and recent loss—are common among these patients.^10,11

Screen chronic pain patients with suicidal ideation for these risk factors. Interventions include:

• aggressively treat associated depression, anxiety, or insomnia
• elicit support from family or other caregivers
• pay close attention to talk about suicide
• hospitalize when necessary
• and, of course, treat pain.

Case continued: No stranger to depression

Ms. A’s psychiatric assessments revealed a pain severity ranking of 9 on a 1-to-10 scale, frequent crying, hopelessness, disrupted sleep, low energy, limited ability to concentrate, and fleeting suicidal thoughts. Her history included counseling during her first marriage and severe depression after separation from her second husband 3 years ago. An 8-week trial of fluoxetine, 20 mg/d, did not improve her depression then.

On examination, she displayed obvious pain behavior, constantly shifting her neck position and moving about the room. Her affect was tearful and her mood depressed. She was taking the NSAID celecoxib, 100 mg bid, and the skeletal muscle relaxant tizanidine, 4 mg tid. She was no longer using opioids and had no history of alcohol or illicit drug abuse.

Based on this assessment, the psychiatrist diagnosed Ms. A as having pain disorder with medical and psychological features, including symptom amplification and depression.

Table 1

4 treatment goals for patients with chronic pain and depression

Educating the patient

As part of your assessment, explain the reciprocal effects of depression and pain. Acknowledge that:

• chronic pain is different from acute pain, although the patient’s pain experience is the same
• treatment often becomes part of the problem in chronic pain.

Doctors tend to apply acute pain treatments chronically, risking long-term effects of polypharmacy to achieve short-term relief. Depressed patients may be more likely than nondepressed patients to receive opioids for chronic pain,¹² and opioids and benzodiazepines may have depressive effects, as reflected by DSM-IV-TR’s inclusion of criteria for “opioid-induced mood disorder” and “sedative-, hypnotic-, or anxiolytic-induced mood disorder.”

To reduce patients’ resistance to antidepressants, reiterate any history of cumulative stressors and affective episodes unrelated to pain. Try using an analogy, such as “stress and pain are like waves on a rock” that eventually damage mood and coping mechanisms, or depression complicating pain is like having “too much on one’s plate.”

Finally, help patients understand that chronic pain is managed, not cured. Encourage them to set treatment goals beyond reducing pain (Table 1) and to make the transition from “patient with pain” to “client managing pain.”

Table 2

Dosing antidepressants and anticonvulsants
for chronic pain and depression

Prescribing principles

Before adding any new pain medications, consider reducing dosages or discontinuing opioids or benzodiazepines and other substances the patient may be taking. Opioid use is associated with risks of dependence, addiction, and side effects including somnolence, cognitive impairment, and reduced activity that amplify depressive symptoms.

Benzodiazepines can generally be tapered by 10% per day, although you may need to extend the final taper over 3 to 4 days or longer, depending upon chronicity of use. Opioids may be tapered by 20% over 5 to 7 days. Breakthrough doses may be needed for marked withdrawal symptoms. Converting to longer half-life agents—such as clonazepam for benzodiazepines or methadone for opioids—often aids tapering, although other agents and strategies exist.¹³

To gauge patient attempts at self-medication, monitor use of alcohol or illicit drugs with urine screening. For patients with a substantial history of substance abuse or positive toxicology screens, monitor randomly every 2 to 4 weeks.

On the other hand, undertreated pain also may impair mood and function.¹ If pain and mood improve and problematic drug-related behaviors resolve with increased opioid analgesia, consider maintaining opioids with regular re-evaluation of mood, coping, and medication adherence.¹¹ Transfer from immediate-release to controlled-release opioids to reduce dosing frequency, clockwatching, and the likelihood of inter-dose pain escalation. In general, maintain and optimize the dosage of nonaddictive analgesics such as NSAIDs, anticonvulsants, or antidepressants.

Case continued: Switching medication

The psychiatrist started Ms. A on nortriptyline, 25 mg at bedtime, to be increased after 3 nights to 50 mg at bedtime. Tizanidine, which had been ineffective, was discontinued to reduce the risk of xerostomia and oversedation in combination with nortriptyline. If tolerated, nortriptyline was to be further increased by 25 mg every 3 days to an initial target dosage of 100 mg at bedtime. The psychiatrist explained to Ms. A that it might take 4 to 6 weeks to gauge the medication’s efficacy.

Psychoeducation addressed the importance of stress reduction, prioritizing commitments, and setting limits on other people’s expectations. The door was left open to future psychotherapeutic exploration of past cumulative stressors.

Because antidepressants may provide an analgesic effect,^6,14 they are often used to treat affective symptoms in chronic pain. Headache and neuralgia tend to respond to antidepressants more robustly than do arthritis and low-back pain. Although some patients respond to low-dose antidepressants, a definitive trial requires full doses for 6 to 8 weeks (Table 2).

Matching a patient’s symptoms with medication side effects is useful when choosing antidepressants (Table 3). So-called “adverse” effects may have a corresponding benefit, depending on the clinical presentation. For example, a moreactivating antidepressant—such as the selective serotonin reuptake inhibitor (SSRI) fluoxetine—may help a patient with fatigue, whereas a moresedating agent—such as a tricyclic antidepressant (TCA) or mirtazapine—may improve sleep for a patient with insomnia.

Psychosocial therapies such as cognitive-behavioral therapy (CBT) or relaxation training (Table 4) may help patients with chronic pain to:

• process covert emotions such as fear and anger as well as guilt, loss, and disability
• reduce somatic preoccupation that is aggravating the pain
• adhere to treatment.

Evidence strongly supports using relaxation techniques to reduce chronic pain in many medical conditions and hypnosis to ameliorate cancer pain. CBT and biofeedback appear moderately effective in relieving chronic pain.¹⁵ CBT is significantly more effective than waiting list control conditions for relieving chronic nonheadache pain in measures of pain experience, mood/affect, cognitive coping and appraisal, pain behavior and activity level, and social role functioning.¹⁶

Pain and opioid medications can impair concentration and affective processing, so initial psychotherapy may need to be supportive while you provide other treatments and simplify medication regimens. Eventually the patient may be ready to address underlying issues that may be contributing to the pain syndrome, such as a history of abuse. However, it is important to address this potentially destabilizing subject only after carefully gauging a patient’s defenses and readiness.

Case continued: A bump in the road

The psychiatrist saw Ms. A 18 months later. Interim history revealed that her pain and mood improved on nortriptyline, 100 mg at bedtime. When she stopped taking nortriptyline 5 months earlier, her neck pain increased and she experienced a “deep blue mood.” Her physician restarted the nortriptyline.

At follow up, Ms. A reported no depressive symptoms and very little neck pain. The psychiatrist discussed with her depression’s relapse rate and the importance of continuing antidepressant therapy. As Ms. A was feeling much better and functioning normally, the psychiatrist decided additional psychotherapeutic intervention was not necessary.

Antidepressant options

TCAs provide analgesia via descending regulatory pathways by inhibiting serotonin and norepinephrine reuptake.¹⁷ When using TCAs for chronic pain, start with 10 to 25 mg at bedtime and increase by 10 to 25 mg every 3 to 7 days as tolerated. Increase incrementally until the pain responds or to the full antidepressant dosage (Table 2). Drug levels (when available) can help you provide an appropriate trial and monitor the patient’s adherence.

If the pain does not respond after 6 to 8 weeks, consider switching to another dual-action agent such as venlafaxine or to an SSRI.

SNRIs. Venlafaxine is a serotonin and norepineph-rine reuptake inhibitor (SNRI) with less-troublesome side effects than TCAs. It is structurally similar to tramadol¹⁸ and has combined serotonin and norepinephrine inhibition at dosages >75 mg/d. Although venlafaxine is not indicated for chronic pain, some studies have suggested possible benefits, including long-term analgesia, reduced polyneuropathic pain, and migraine prophylaxis.^19-21 Venlafaxine may be a reasonable first or second choice for treating depression in patients with chronic pain, especially headache.¹⁴

Duloxetine—another SNRI—awaits FDA approval. Some studies have suggested that duloxetine improves painful physical symptoms as well as mood and functioning in major depression.²²

SSRIs may be effective for certain types of pain, but the evidence is conflicting. Results of 41controlled trials support TCAs’ analgesic efficacy for neuropathic pain, headache, and central and post-stroke pain, whereas SSRIs’ analgesic efficacy varies from study to study. Comparisons of TCAs and SSRIs as analgesics uniformly show TCAs to be more effective, with the SSRIs often showing no analgesic effect.

Of three controlled trials of SSRIs for diabetic neuropathy, one showed fluoxetine similar to placebo, and two smaller studies showed paroxetine and citalopram more effective than placebo. Fluoxetine has shown analgesic effect for fibromyalgia in one study, but no effect in another. Citalopram showed no analgesic effect for fibromyalgia in another study.²³

A prospective, double-blind study comparing fluoxetine, sertraline, paroxetine, and venlafaxine for migraines reported moderate to significant improvement in less than one-half of SSRI-treated patients vs two-thirds of venlafaxine-treated patients.²¹ SSRIs are no longer recognized by the International Headache Society as primary preventative medications for migraine.

Fluoxetine may help chronic daily headache, and paroxetine and citalopram may be useful for diabetic neuropathy. However, one cannot generalize that all SSRIs are similarly effective as analgesics.¹⁴

SSRIs have fewer side effects than TCAs and are less dangerous in overdose. In general, however, SSRIs are a second-line treatment for pain, to be used when dual-action agents pose disadvantageous side effects (Table 3) or have been poorly tolerated or ineffective.

Table 3

Antidepressant side effects:
Limitations and potential benefits in chronic pain

Table 4

How psychosocial therapies can help treat chronic pain and depression

Monoamine oxidase inhibitors (MAOIs) may have some efficacy for neuropathy and headache, but the need for a tyramine-free diet and potential for drug-drug interactions limit their usefulness. Co-administering an MAOI and meperidine is always contraindicated, as this combination can produce fever, delirium, seizures, circulatory collapse, and death. Similarly, avoid using an MAOI with any other antidepressant.

Others. Evidence is very limited on using other antidepressants such as trazodone, nefazodone, bupropion, and mirtazapine in chronic pain:

• Trazodone may help pediatric migraine, but it is not a consistent analgesic and may not be well-tolerated.
• Case reports suggest bupropion may help with headaches and chronic low-back pain.¹⁴
• Mirtazapine and trazodone may be useful adjuncts for treating insomnia in depressed patients with chronic pain.

Other options

Anticonvulsants appear useful for neuropathic pain and are appropriate for chronic pain patients who cannot tolerate TCAs.²⁴ Like TCAs, anticonvulsants are not addictive. Unlike TCAs, anticonvulsants may help stabilize other affective illnesses that may coexist with chronic pain, including bipolar disorder, schizoaffective disorder, and impulsivity/aggression related to dementia or personality disorder.⁶ If the starting dosage is not effective within 1 week, increase gradually every 2 to 3 days to target dosages comparable to those for anticonvulsant efficacy.

Carbamazepine and gabapentin are recommended first-line medications for neuropathy. Carbamazepine is indicated for treating trigeminal neuralgia, although its cytochrome P-450 3A3/4 isoenzyme induction may reduce serum levels of acetaminophen, opioids, and oral contraceptives. Gabapentin, although not clearly beneficial for bipolar disorder, has anxiolytic effects and a benign side-effect profile, which may help patients with chronic pain.

Valproate can help prevent migraines. Clonazepam can help reduce anxiety and restless legs syndrome but may be habituating. Anticonvulsants’ common adverse effects include sedation, GI upset, dizziness, and fatigue.

Lithium has known efficacy for mood stabilization in bipolar disorder and can ameliorate cluster headaches.

Antipsychotics. Evidence is sparse on whether antipsychotics have analgesic activity. Their side effects generally limit their usefulness to treating pain in patients with psychosis or delirium.⁶

Stimulants such as dextroamphetamine and methylphenidate can be helpful adjuncts for treating depression, especially for medical inpatients who require a rapid therapeutic response. Stimulants may reduce fatigue or excessive sedation and improve concentration in patients receiving opioids for chronic pain. They also may have analgesic effects when combined with opioids. Potential adverse effects include appetite suppression, anxiety or agitation, confusion, tics, and addiction.⁶

Precautions. The muscle relaxant carisoprodol is associated with potential dependence and withdrawal. Cyclobenzaprine, another muscle relaxant, has a TCA-like structure and can be lethal in overdose. Baclofen can be useful for chronic pain related to spasticity, although psychotic depression and mania have been reported with abrupt withdrawal.⁶

Related resources

• American Academy of Pain Medicine. www.painmed.org/
• American Academy of Pain Management. www.aapainmanage.org
• Pain.com: continuing medical education for anesthesiology professionals. www.pain.com/index.cfm
• Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;13:345-56

Drug brand names

• Amitriptyline • Elavil
• Baclofen • Lioresal
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Carisoprodol • Soma
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Dihydrocodeine • Synalgos-DC
• Doxepin • Sinequan
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Hydrocodone • Vicodin, Lortab
• Imipramine • Tofranil
• Lithium • Eskalith CR, Lithobid
• Maprotiline • Ludiomil
• Meperidine • Demerol
• Methadone • Dolophine
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tizanidine • Zanaflex
• Tramadol • Ultram
• Trazodone • Desyrel
• Valproate • Depakote
• Venlafaxine • Effexor, Effexor XR

Disclosure

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

Ms. A, age 44, fell from a 3-foot stool while reaching for a high kitchen shelf and suffered severe neck flexion. Her initial pain persisted for weeks and then months, resulting in chronic neck pain aggravated by movement.

Over the past year, her doctor has prescribed numerous analgesics and muscle relaxants, including tramadol, hydrocodone, oxycodone, tizanidine, and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatments at a pain clinic have included triggerpoint injections, cervical epidural corticosteroid injection, left-sided cervical medial branch blocks, transcutaneous electrical nerve stimulation, and physical therapy. None provided sustained relief.

During a pain clinic visit, Ms. A wept and said she was tired of living with pain. She acknowledged depression and agreed to psychiatric consultation.

As in Ms. A’s case, physicians often refer patients with chronic pain and affective symptoms for psychiatric evaluation. These patients are often fearful, angry, and suspicious of any suggestion that their physical discomfort has a psychiatric component. They typically believe their pain had a clear onset and therefore should have an end point. Many have experienced unproductive specialty evaluations and failed treatments.

To help you overcome these obstacles when treating patients with chronic pain and depression, we discuss:

• strategies to gain patients’ trust and build a therapeutic alliance
• how to assess their pain, depression, and suicide risk
• the role of psychotherapy in treating chronic pain
• and evidence for choosing effective, nonaddicting medications.

Psychiatric evaluation

Depression and pain are linked psychologically and biochemically, sharing neurotransmitters involved in both nociceptive pathways and mood, especially serotonin and norepinephrine.^1,2 One-third to one-half of patients with chronic pain report comorbid depression,³ and more than one-half of depressed patients presenting to primary care physicians report only somatic symptoms—various pain complaints among the most common.^4,5

Primary care doctors tend to refer chronic pain and depression cases to psychiatrists when:

• patients are preoccupied with medication, have not followed treatment recommendations, or do not respond to treatment as expected
• extensive medical evaluations reveal few or equivocal findings
• somatic complaints are vague and diffuse, or there is marked disparity between pain complaints/disability and objective findings.^6,7

Assessing pain. In the initial assessment, validate the patient’s pain experience by asking about the location, quality, and severity of pain. The visual analogue scale (VAS) is commonly used to measure pain severity. The patient marks a spot on a line from “no pain” to “worst possible pain,” or—on a numbered VAS—from 0 (no pain) to 10 (extreme pain). The least and most severe pain over the preceding month can be ranked as baseline values.⁸

Be sensitive to the patient’s fear that you will attribute the pain to psychosocial issues or imply that “the pain is in your head.” Emphasize that you intend to evaluate the “whole person,” not just the part that hurts. Focus on how the pain affects the patient’s lifestyle—rather than its cause—and explore medication use patterns.

Assessing depression. The word “depression” is emotionally charged for chronic pain patients, who view affective symptoms—if they acknowledge them at all—as secondary to pain. They may strongly resist treatment for anything but pain. One way to defuse this defensiveness is to avoid attributing the pain to stress or depression.

Begin by assessing vegetative symptoms, which overlap in chronic pain and depression. The Beck Depression Inventory-II (Beck-II) may be a useful screening tool in a busy practice; the short form (13 questions) takes about 5 minutes to complete.⁹

Explore cognitive and behavioral symptoms such as concentration, pleasure and interest level, activity, and self-esteem. Review the chronology of pain onset, mood changes, and stressors (proximate, remote, and cumulative).

Seek clues to endogenous factors by asking about past affective episodes, response to antidepressants, and family history of psychopathology. Substances that may induce depression include reserpine, interferon, and antiparkinsonian agents. Screen for potential organic mood disorders, such as depression secondary to hypothyroidism, corticosteroid use, Parkinson’s disease, lupus, HIV infection, or cerebrovascular disease. Where appropriate, obtain collateral information from family or friends.

Assessing suicide risk. Chronic pain patients may be at greater risk of suicide than the general population. Besides pain, other risk factors for suicide—such as major depression, anxiety disorders, alcohol/substance abuse, sleep disturbances, male gender, diminished social support, and recent loss—are common among these patients.^10,11

Screen chronic pain patients with suicidal ideation for these risk factors. Interventions include:

• aggressively treat associated depression, anxiety, or insomnia
• elicit support from family or other caregivers
• pay close attention to talk about suicide
• hospitalize when necessary
• and, of course, treat pain.

Case continued: No stranger to depression

Ms. A’s psychiatric assessments revealed a pain severity ranking of 9 on a 1-to-10 scale, frequent crying, hopelessness, disrupted sleep, low energy, limited ability to concentrate, and fleeting suicidal thoughts. Her history included counseling during her first marriage and severe depression after separation from her second husband 3 years ago. An 8-week trial of fluoxetine, 20 mg/d, did not improve her depression then.

On examination, she displayed obvious pain behavior, constantly shifting her neck position and moving about the room. Her affect was tearful and her mood depressed. She was taking the NSAID celecoxib, 100 mg bid, and the skeletal muscle relaxant tizanidine, 4 mg tid. She was no longer using opioids and had no history of alcohol or illicit drug abuse.

Based on this assessment, the psychiatrist diagnosed Ms. A as having pain disorder with medical and psychological features, including symptom amplification and depression.

Table 1

4 treatment goals for patients with chronic pain and depression

Educating the patient

As part of your assessment, explain the reciprocal effects of depression and pain. Acknowledge that:

• chronic pain is different from acute pain, although the patient’s pain experience is the same
• treatment often becomes part of the problem in chronic pain.

Doctors tend to apply acute pain treatments chronically, risking long-term effects of polypharmacy to achieve short-term relief. Depressed patients may be more likely than nondepressed patients to receive opioids for chronic pain,¹² and opioids and benzodiazepines may have depressive effects, as reflected by DSM-IV-TR’s inclusion of criteria for “opioid-induced mood disorder” and “sedative-, hypnotic-, or anxiolytic-induced mood disorder.”

To reduce patients’ resistance to antidepressants, reiterate any history of cumulative stressors and affective episodes unrelated to pain. Try using an analogy, such as “stress and pain are like waves on a rock” that eventually damage mood and coping mechanisms, or depression complicating pain is like having “too much on one’s plate.”

Finally, help patients understand that chronic pain is managed, not cured. Encourage them to set treatment goals beyond reducing pain (Table 1) and to make the transition from “patient with pain” to “client managing pain.”

Table 2

Dosing antidepressants and anticonvulsants
for chronic pain and depression

Prescribing principles

Before adding any new pain medications, consider reducing dosages or discontinuing opioids or benzodiazepines and other substances the patient may be taking. Opioid use is associated with risks of dependence, addiction, and side effects including somnolence, cognitive impairment, and reduced activity that amplify depressive symptoms.

Benzodiazepines can generally be tapered by 10% per day, although you may need to extend the final taper over 3 to 4 days or longer, depending upon chronicity of use. Opioids may be tapered by 20% over 5 to 7 days. Breakthrough doses may be needed for marked withdrawal symptoms. Converting to longer half-life agents—such as clonazepam for benzodiazepines or methadone for opioids—often aids tapering, although other agents and strategies exist.¹³

To gauge patient attempts at self-medication, monitor use of alcohol or illicit drugs with urine screening. For patients with a substantial history of substance abuse or positive toxicology screens, monitor randomly every 2 to 4 weeks.

On the other hand, undertreated pain also may impair mood and function.¹ If pain and mood improve and problematic drug-related behaviors resolve with increased opioid analgesia, consider maintaining opioids with regular re-evaluation of mood, coping, and medication adherence.¹¹ Transfer from immediate-release to controlled-release opioids to reduce dosing frequency, clockwatching, and the likelihood of inter-dose pain escalation. In general, maintain and optimize the dosage of nonaddictive analgesics such as NSAIDs, anticonvulsants, or antidepressants.

Case continued: Switching medication

The psychiatrist started Ms. A on nortriptyline, 25 mg at bedtime, to be increased after 3 nights to 50 mg at bedtime. Tizanidine, which had been ineffective, was discontinued to reduce the risk of xerostomia and oversedation in combination with nortriptyline. If tolerated, nortriptyline was to be further increased by 25 mg every 3 days to an initial target dosage of 100 mg at bedtime. The psychiatrist explained to Ms. A that it might take 4 to 6 weeks to gauge the medication’s efficacy.

Psychoeducation addressed the importance of stress reduction, prioritizing commitments, and setting limits on other people’s expectations. The door was left open to future psychotherapeutic exploration of past cumulative stressors.

Because antidepressants may provide an analgesic effect,^6,14 they are often used to treat affective symptoms in chronic pain. Headache and neuralgia tend to respond to antidepressants more robustly than do arthritis and low-back pain. Although some patients respond to low-dose antidepressants, a definitive trial requires full doses for 6 to 8 weeks (Table 2).

Matching a patient’s symptoms with medication side effects is useful when choosing antidepressants (Table 3). So-called “adverse” effects may have a corresponding benefit, depending on the clinical presentation. For example, a moreactivating antidepressant—such as the selective serotonin reuptake inhibitor (SSRI) fluoxetine—may help a patient with fatigue, whereas a moresedating agent—such as a tricyclic antidepressant (TCA) or mirtazapine—may improve sleep for a patient with insomnia.

Psychosocial therapies such as cognitive-behavioral therapy (CBT) or relaxation training (Table 4) may help patients with chronic pain to:

• process covert emotions such as fear and anger as well as guilt, loss, and disability
• reduce somatic preoccupation that is aggravating the pain
• adhere to treatment.

Evidence strongly supports using relaxation techniques to reduce chronic pain in many medical conditions and hypnosis to ameliorate cancer pain. CBT and biofeedback appear moderately effective in relieving chronic pain.¹⁵ CBT is significantly more effective than waiting list control conditions for relieving chronic nonheadache pain in measures of pain experience, mood/affect, cognitive coping and appraisal, pain behavior and activity level, and social role functioning.¹⁶

Pain and opioid medications can impair concentration and affective processing, so initial psychotherapy may need to be supportive while you provide other treatments and simplify medication regimens. Eventually the patient may be ready to address underlying issues that may be contributing to the pain syndrome, such as a history of abuse. However, it is important to address this potentially destabilizing subject only after carefully gauging a patient’s defenses and readiness.

Case continued: A bump in the road

The psychiatrist saw Ms. A 18 months later. Interim history revealed that her pain and mood improved on nortriptyline, 100 mg at bedtime. When she stopped taking nortriptyline 5 months earlier, her neck pain increased and she experienced a “deep blue mood.” Her physician restarted the nortriptyline.

At follow up, Ms. A reported no depressive symptoms and very little neck pain. The psychiatrist discussed with her depression’s relapse rate and the importance of continuing antidepressant therapy. As Ms. A was feeling much better and functioning normally, the psychiatrist decided additional psychotherapeutic intervention was not necessary.

Antidepressant options

TCAs provide analgesia via descending regulatory pathways by inhibiting serotonin and norepinephrine reuptake.¹⁷ When using TCAs for chronic pain, start with 10 to 25 mg at bedtime and increase by 10 to 25 mg every 3 to 7 days as tolerated. Increase incrementally until the pain responds or to the full antidepressant dosage (Table 2). Drug levels (when available) can help you provide an appropriate trial and monitor the patient’s adherence.

If the pain does not respond after 6 to 8 weeks, consider switching to another dual-action agent such as venlafaxine or to an SSRI.

SNRIs. Venlafaxine is a serotonin and norepineph-rine reuptake inhibitor (SNRI) with less-troublesome side effects than TCAs. It is structurally similar to tramadol¹⁸ and has combined serotonin and norepinephrine inhibition at dosages >75 mg/d. Although venlafaxine is not indicated for chronic pain, some studies have suggested possible benefits, including long-term analgesia, reduced polyneuropathic pain, and migraine prophylaxis.^19-21 Venlafaxine may be a reasonable first or second choice for treating depression in patients with chronic pain, especially headache.¹⁴

Duloxetine—another SNRI—awaits FDA approval. Some studies have suggested that duloxetine improves painful physical symptoms as well as mood and functioning in major depression.²²

SSRIs may be effective for certain types of pain, but the evidence is conflicting. Results of 41controlled trials support TCAs’ analgesic efficacy for neuropathic pain, headache, and central and post-stroke pain, whereas SSRIs’ analgesic efficacy varies from study to study. Comparisons of TCAs and SSRIs as analgesics uniformly show TCAs to be more effective, with the SSRIs often showing no analgesic effect.

Of three controlled trials of SSRIs for diabetic neuropathy, one showed fluoxetine similar to placebo, and two smaller studies showed paroxetine and citalopram more effective than placebo. Fluoxetine has shown analgesic effect for fibromyalgia in one study, but no effect in another. Citalopram showed no analgesic effect for fibromyalgia in another study.²³

A prospective, double-blind study comparing fluoxetine, sertraline, paroxetine, and venlafaxine for migraines reported moderate to significant improvement in less than one-half of SSRI-treated patients vs two-thirds of venlafaxine-treated patients.²¹ SSRIs are no longer recognized by the International Headache Society as primary preventative medications for migraine.

Fluoxetine may help chronic daily headache, and paroxetine and citalopram may be useful for diabetic neuropathy. However, one cannot generalize that all SSRIs are similarly effective as analgesics.¹⁴

SSRIs have fewer side effects than TCAs and are less dangerous in overdose. In general, however, SSRIs are a second-line treatment for pain, to be used when dual-action agents pose disadvantageous side effects (Table 3) or have been poorly tolerated or ineffective.

Table 3

Antidepressant side effects:
Limitations and potential benefits in chronic pain

Table 4

How psychosocial therapies can help treat chronic pain and depression

Monoamine oxidase inhibitors (MAOIs) may have some efficacy for neuropathy and headache, but the need for a tyramine-free diet and potential for drug-drug interactions limit their usefulness. Co-administering an MAOI and meperidine is always contraindicated, as this combination can produce fever, delirium, seizures, circulatory collapse, and death. Similarly, avoid using an MAOI with any other antidepressant.

Others. Evidence is very limited on using other antidepressants such as trazodone, nefazodone, bupropion, and mirtazapine in chronic pain:

• Trazodone may help pediatric migraine, but it is not a consistent analgesic and may not be well-tolerated.
• Case reports suggest bupropion may help with headaches and chronic low-back pain.¹⁴
• Mirtazapine and trazodone may be useful adjuncts for treating insomnia in depressed patients with chronic pain.

Other options

Anticonvulsants appear useful for neuropathic pain and are appropriate for chronic pain patients who cannot tolerate TCAs.²⁴ Like TCAs, anticonvulsants are not addictive. Unlike TCAs, anticonvulsants may help stabilize other affective illnesses that may coexist with chronic pain, including bipolar disorder, schizoaffective disorder, and impulsivity/aggression related to dementia or personality disorder.⁶ If the starting dosage is not effective within 1 week, increase gradually every 2 to 3 days to target dosages comparable to those for anticonvulsant efficacy.

Carbamazepine and gabapentin are recommended first-line medications for neuropathy. Carbamazepine is indicated for treating trigeminal neuralgia, although its cytochrome P-450 3A3/4 isoenzyme induction may reduce serum levels of acetaminophen, opioids, and oral contraceptives. Gabapentin, although not clearly beneficial for bipolar disorder, has anxiolytic effects and a benign side-effect profile, which may help patients with chronic pain.

Valproate can help prevent migraines. Clonazepam can help reduce anxiety and restless legs syndrome but may be habituating. Anticonvulsants’ common adverse effects include sedation, GI upset, dizziness, and fatigue.

Lithium has known efficacy for mood stabilization in bipolar disorder and can ameliorate cluster headaches.

Antipsychotics. Evidence is sparse on whether antipsychotics have analgesic activity. Their side effects generally limit their usefulness to treating pain in patients with psychosis or delirium.⁶

Stimulants such as dextroamphetamine and methylphenidate can be helpful adjuncts for treating depression, especially for medical inpatients who require a rapid therapeutic response. Stimulants may reduce fatigue or excessive sedation and improve concentration in patients receiving opioids for chronic pain. They also may have analgesic effects when combined with opioids. Potential adverse effects include appetite suppression, anxiety or agitation, confusion, tics, and addiction.⁶

Precautions. The muscle relaxant carisoprodol is associated with potential dependence and withdrawal. Cyclobenzaprine, another muscle relaxant, has a TCA-like structure and can be lethal in overdose. Baclofen can be useful for chronic pain related to spasticity, although psychotic depression and mania have been reported with abrupt withdrawal.⁶

Related resources

• American Academy of Pain Medicine. www.painmed.org/
• American Academy of Pain Management. www.aapainmanage.org
• Pain.com: continuing medical education for anesthesiology professionals. www.pain.com/index.cfm
• Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;13:345-56

Drug brand names

• Amitriptyline • Elavil
• Baclofen • Lioresal
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Carisoprodol • Soma
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Dihydrocodeine • Synalgos-DC
• Doxepin • Sinequan
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Hydrocodone • Vicodin, Lortab
• Imipramine • Tofranil
• Lithium • Eskalith CR, Lithobid
• Maprotiline • Ludiomil
• Meperidine • Demerol
• Methadone • Dolophine
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tizanidine • Zanaflex
• Tramadol • Ultram
• Trazodone • Desyrel
• Valproate • Depakote
• Venlafaxine • Effexor, Effexor XR

Disclosure

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

Ms. A, age 44, fell from a 3-foot stool while reaching for a high kitchen shelf and suffered severe neck flexion. Her initial pain persisted for weeks and then months, resulting in chronic neck pain aggravated by movement.

Over the past year, her doctor has prescribed numerous analgesics and muscle relaxants, including tramadol, hydrocodone, oxycodone, tizanidine, and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatments at a pain clinic have included triggerpoint injections, cervical epidural corticosteroid injection, left-sided cervical medial branch blocks, transcutaneous electrical nerve stimulation, and physical therapy. None provided sustained relief.

During a pain clinic visit, Ms. A wept and said she was tired of living with pain. She acknowledged depression and agreed to psychiatric consultation.

As in Ms. A’s case, physicians often refer patients with chronic pain and affective symptoms for psychiatric evaluation. These patients are often fearful, angry, and suspicious of any suggestion that their physical discomfort has a psychiatric component. They typically believe their pain had a clear onset and therefore should have an end point. Many have experienced unproductive specialty evaluations and failed treatments.

To help you overcome these obstacles when treating patients with chronic pain and depression, we discuss:

• strategies to gain patients’ trust and build a therapeutic alliance
• how to assess their pain, depression, and suicide risk
• the role of psychotherapy in treating chronic pain
• and evidence for choosing effective, nonaddicting medications.

Psychiatric evaluation

Depression and pain are linked psychologically and biochemically, sharing neurotransmitters involved in both nociceptive pathways and mood, especially serotonin and norepinephrine.^1,2 One-third to one-half of patients with chronic pain report comorbid depression,³ and more than one-half of depressed patients presenting to primary care physicians report only somatic symptoms—various pain complaints among the most common.^4,5

Primary care doctors tend to refer chronic pain and depression cases to psychiatrists when:

• patients are preoccupied with medication, have not followed treatment recommendations, or do not respond to treatment as expected
• extensive medical evaluations reveal few or equivocal findings
• somatic complaints are vague and diffuse, or there is marked disparity between pain complaints/disability and objective findings.^6,7

Assessing pain. In the initial assessment, validate the patient’s pain experience by asking about the location, quality, and severity of pain. The visual analogue scale (VAS) is commonly used to measure pain severity. The patient marks a spot on a line from “no pain” to “worst possible pain,” or—on a numbered VAS—from 0 (no pain) to 10 (extreme pain). The least and most severe pain over the preceding month can be ranked as baseline values.⁸

Be sensitive to the patient’s fear that you will attribute the pain to psychosocial issues or imply that “the pain is in your head.” Emphasize that you intend to evaluate the “whole person,” not just the part that hurts. Focus on how the pain affects the patient’s lifestyle—rather than its cause—and explore medication use patterns.

Assessing depression. The word “depression” is emotionally charged for chronic pain patients, who view affective symptoms—if they acknowledge them at all—as secondary to pain. They may strongly resist treatment for anything but pain. One way to defuse this defensiveness is to avoid attributing the pain to stress or depression.

Begin by assessing vegetative symptoms, which overlap in chronic pain and depression. The Beck Depression Inventory-II (Beck-II) may be a useful screening tool in a busy practice; the short form (13 questions) takes about 5 minutes to complete.⁹

Explore cognitive and behavioral symptoms such as concentration, pleasure and interest level, activity, and self-esteem. Review the chronology of pain onset, mood changes, and stressors (proximate, remote, and cumulative).

Seek clues to endogenous factors by asking about past affective episodes, response to antidepressants, and family history of psychopathology. Substances that may induce depression include reserpine, interferon, and antiparkinsonian agents. Screen for potential organic mood disorders, such as depression secondary to hypothyroidism, corticosteroid use, Parkinson’s disease, lupus, HIV infection, or cerebrovascular disease. Where appropriate, obtain collateral information from family or friends.

Assessing suicide risk. Chronic pain patients may be at greater risk of suicide than the general population. Besides pain, other risk factors for suicide—such as major depression, anxiety disorders, alcohol/substance abuse, sleep disturbances, male gender, diminished social support, and recent loss—are common among these patients.^10,11

Screen chronic pain patients with suicidal ideation for these risk factors. Interventions include:

• aggressively treat associated depression, anxiety, or insomnia
• elicit support from family or other caregivers
• pay close attention to talk about suicide
• hospitalize when necessary
• and, of course, treat pain.

Case continued: No stranger to depression

Ms. A’s psychiatric assessments revealed a pain severity ranking of 9 on a 1-to-10 scale, frequent crying, hopelessness, disrupted sleep, low energy, limited ability to concentrate, and fleeting suicidal thoughts. Her history included counseling during her first marriage and severe depression after separation from her second husband 3 years ago. An 8-week trial of fluoxetine, 20 mg/d, did not improve her depression then.

On examination, she displayed obvious pain behavior, constantly shifting her neck position and moving about the room. Her affect was tearful and her mood depressed. She was taking the NSAID celecoxib, 100 mg bid, and the skeletal muscle relaxant tizanidine, 4 mg tid. She was no longer using opioids and had no history of alcohol or illicit drug abuse.

Based on this assessment, the psychiatrist diagnosed Ms. A as having pain disorder with medical and psychological features, including symptom amplification and depression.

Table 1

4 treatment goals for patients with chronic pain and depression

Educating the patient

As part of your assessment, explain the reciprocal effects of depression and pain. Acknowledge that:

• chronic pain is different from acute pain, although the patient’s pain experience is the same
• treatment often becomes part of the problem in chronic pain.

Doctors tend to apply acute pain treatments chronically, risking long-term effects of polypharmacy to achieve short-term relief. Depressed patients may be more likely than nondepressed patients to receive opioids for chronic pain,¹² and opioids and benzodiazepines may have depressive effects, as reflected by DSM-IV-TR’s inclusion of criteria for “opioid-induced mood disorder” and “sedative-, hypnotic-, or anxiolytic-induced mood disorder.”

To reduce patients’ resistance to antidepressants, reiterate any history of cumulative stressors and affective episodes unrelated to pain. Try using an analogy, such as “stress and pain are like waves on a rock” that eventually damage mood and coping mechanisms, or depression complicating pain is like having “too much on one’s plate.”

Finally, help patients understand that chronic pain is managed, not cured. Encourage them to set treatment goals beyond reducing pain (Table 1) and to make the transition from “patient with pain” to “client managing pain.”

Table 2

Dosing antidepressants and anticonvulsants
for chronic pain and depression

Prescribing principles

Before adding any new pain medications, consider reducing dosages or discontinuing opioids or benzodiazepines and other substances the patient may be taking. Opioid use is associated with risks of dependence, addiction, and side effects including somnolence, cognitive impairment, and reduced activity that amplify depressive symptoms.

Benzodiazepines can generally be tapered by 10% per day, although you may need to extend the final taper over 3 to 4 days or longer, depending upon chronicity of use. Opioids may be tapered by 20% over 5 to 7 days. Breakthrough doses may be needed for marked withdrawal symptoms. Converting to longer half-life agents—such as clonazepam for benzodiazepines or methadone for opioids—often aids tapering, although other agents and strategies exist.¹³

To gauge patient attempts at self-medication, monitor use of alcohol or illicit drugs with urine screening. For patients with a substantial history of substance abuse or positive toxicology screens, monitor randomly every 2 to 4 weeks.

On the other hand, undertreated pain also may impair mood and function.¹ If pain and mood improve and problematic drug-related behaviors resolve with increased opioid analgesia, consider maintaining opioids with regular re-evaluation of mood, coping, and medication adherence.¹¹ Transfer from immediate-release to controlled-release opioids to reduce dosing frequency, clockwatching, and the likelihood of inter-dose pain escalation. In general, maintain and optimize the dosage of nonaddictive analgesics such as NSAIDs, anticonvulsants, or antidepressants.

Case continued: Switching medication

The psychiatrist started Ms. A on nortriptyline, 25 mg at bedtime, to be increased after 3 nights to 50 mg at bedtime. Tizanidine, which had been ineffective, was discontinued to reduce the risk of xerostomia and oversedation in combination with nortriptyline. If tolerated, nortriptyline was to be further increased by 25 mg every 3 days to an initial target dosage of 100 mg at bedtime. The psychiatrist explained to Ms. A that it might take 4 to 6 weeks to gauge the medication’s efficacy.

Psychoeducation addressed the importance of stress reduction, prioritizing commitments, and setting limits on other people’s expectations. The door was left open to future psychotherapeutic exploration of past cumulative stressors.

Because antidepressants may provide an analgesic effect,^6,14 they are often used to treat affective symptoms in chronic pain. Headache and neuralgia tend to respond to antidepressants more robustly than do arthritis and low-back pain. Although some patients respond to low-dose antidepressants, a definitive trial requires full doses for 6 to 8 weeks (Table 2).

Matching a patient’s symptoms with medication side effects is useful when choosing antidepressants (Table 3). So-called “adverse” effects may have a corresponding benefit, depending on the clinical presentation. For example, a moreactivating antidepressant—such as the selective serotonin reuptake inhibitor (SSRI) fluoxetine—may help a patient with fatigue, whereas a moresedating agent—such as a tricyclic antidepressant (TCA) or mirtazapine—may improve sleep for a patient with insomnia.

Psychosocial therapies such as cognitive-behavioral therapy (CBT) or relaxation training (Table 4) may help patients with chronic pain to:

• process covert emotions such as fear and anger as well as guilt, loss, and disability
• reduce somatic preoccupation that is aggravating the pain
• adhere to treatment.

Evidence strongly supports using relaxation techniques to reduce chronic pain in many medical conditions and hypnosis to ameliorate cancer pain. CBT and biofeedback appear moderately effective in relieving chronic pain.¹⁵ CBT is significantly more effective than waiting list control conditions for relieving chronic nonheadache pain in measures of pain experience, mood/affect, cognitive coping and appraisal, pain behavior and activity level, and social role functioning.¹⁶

Pain and opioid medications can impair concentration and affective processing, so initial psychotherapy may need to be supportive while you provide other treatments and simplify medication regimens. Eventually the patient may be ready to address underlying issues that may be contributing to the pain syndrome, such as a history of abuse. However, it is important to address this potentially destabilizing subject only after carefully gauging a patient’s defenses and readiness.

Case continued: A bump in the road

The psychiatrist saw Ms. A 18 months later. Interim history revealed that her pain and mood improved on nortriptyline, 100 mg at bedtime. When she stopped taking nortriptyline 5 months earlier, her neck pain increased and she experienced a “deep blue mood.” Her physician restarted the nortriptyline.

At follow up, Ms. A reported no depressive symptoms and very little neck pain. The psychiatrist discussed with her depression’s relapse rate and the importance of continuing antidepressant therapy. As Ms. A was feeling much better and functioning normally, the psychiatrist decided additional psychotherapeutic intervention was not necessary.

Antidepressant options

TCAs provide analgesia via descending regulatory pathways by inhibiting serotonin and norepinephrine reuptake.¹⁷ When using TCAs for chronic pain, start with 10 to 25 mg at bedtime and increase by 10 to 25 mg every 3 to 7 days as tolerated. Increase incrementally until the pain responds or to the full antidepressant dosage (Table 2). Drug levels (when available) can help you provide an appropriate trial and monitor the patient’s adherence.

If the pain does not respond after 6 to 8 weeks, consider switching to another dual-action agent such as venlafaxine or to an SSRI.

SNRIs. Venlafaxine is a serotonin and norepineph-rine reuptake inhibitor (SNRI) with less-troublesome side effects than TCAs. It is structurally similar to tramadol¹⁸ and has combined serotonin and norepinephrine inhibition at dosages >75 mg/d. Although venlafaxine is not indicated for chronic pain, some studies have suggested possible benefits, including long-term analgesia, reduced polyneuropathic pain, and migraine prophylaxis.^19-21 Venlafaxine may be a reasonable first or second choice for treating depression in patients with chronic pain, especially headache.¹⁴

Duloxetine—another SNRI—awaits FDA approval. Some studies have suggested that duloxetine improves painful physical symptoms as well as mood and functioning in major depression.²²

SSRIs may be effective for certain types of pain, but the evidence is conflicting. Results of 41controlled trials support TCAs’ analgesic efficacy for neuropathic pain, headache, and central and post-stroke pain, whereas SSRIs’ analgesic efficacy varies from study to study. Comparisons of TCAs and SSRIs as analgesics uniformly show TCAs to be more effective, with the SSRIs often showing no analgesic effect.

Of three controlled trials of SSRIs for diabetic neuropathy, one showed fluoxetine similar to placebo, and two smaller studies showed paroxetine and citalopram more effective than placebo. Fluoxetine has shown analgesic effect for fibromyalgia in one study, but no effect in another. Citalopram showed no analgesic effect for fibromyalgia in another study.²³

A prospective, double-blind study comparing fluoxetine, sertraline, paroxetine, and venlafaxine for migraines reported moderate to significant improvement in less than one-half of SSRI-treated patients vs two-thirds of venlafaxine-treated patients.²¹ SSRIs are no longer recognized by the International Headache Society as primary preventative medications for migraine.

Fluoxetine may help chronic daily headache, and paroxetine and citalopram may be useful for diabetic neuropathy. However, one cannot generalize that all SSRIs are similarly effective as analgesics.¹⁴

SSRIs have fewer side effects than TCAs and are less dangerous in overdose. In general, however, SSRIs are a second-line treatment for pain, to be used when dual-action agents pose disadvantageous side effects (Table 3) or have been poorly tolerated or ineffective.

Table 3

Antidepressant side effects:
Limitations and potential benefits in chronic pain

Table 4

How psychosocial therapies can help treat chronic pain and depression

Monoamine oxidase inhibitors (MAOIs) may have some efficacy for neuropathy and headache, but the need for a tyramine-free diet and potential for drug-drug interactions limit their usefulness. Co-administering an MAOI and meperidine is always contraindicated, as this combination can produce fever, delirium, seizures, circulatory collapse, and death. Similarly, avoid using an MAOI with any other antidepressant.

Others. Evidence is very limited on using other antidepressants such as trazodone, nefazodone, bupropion, and mirtazapine in chronic pain:

• Trazodone may help pediatric migraine, but it is not a consistent analgesic and may not be well-tolerated.
• Case reports suggest bupropion may help with headaches and chronic low-back pain.¹⁴
• Mirtazapine and trazodone may be useful adjuncts for treating insomnia in depressed patients with chronic pain.

Other options

Anticonvulsants appear useful for neuropathic pain and are appropriate for chronic pain patients who cannot tolerate TCAs.²⁴ Like TCAs, anticonvulsants are not addictive. Unlike TCAs, anticonvulsants may help stabilize other affective illnesses that may coexist with chronic pain, including bipolar disorder, schizoaffective disorder, and impulsivity/aggression related to dementia or personality disorder.⁶ If the starting dosage is not effective within 1 week, increase gradually every 2 to 3 days to target dosages comparable to those for anticonvulsant efficacy.

Carbamazepine and gabapentin are recommended first-line medications for neuropathy. Carbamazepine is indicated for treating trigeminal neuralgia, although its cytochrome P-450 3A3/4 isoenzyme induction may reduce serum levels of acetaminophen, opioids, and oral contraceptives. Gabapentin, although not clearly beneficial for bipolar disorder, has anxiolytic effects and a benign side-effect profile, which may help patients with chronic pain.

Valproate can help prevent migraines. Clonazepam can help reduce anxiety and restless legs syndrome but may be habituating. Anticonvulsants’ common adverse effects include sedation, GI upset, dizziness, and fatigue.

Lithium has known efficacy for mood stabilization in bipolar disorder and can ameliorate cluster headaches.

Antipsychotics. Evidence is sparse on whether antipsychotics have analgesic activity. Their side effects generally limit their usefulness to treating pain in patients with psychosis or delirium.⁶

Stimulants such as dextroamphetamine and methylphenidate can be helpful adjuncts for treating depression, especially for medical inpatients who require a rapid therapeutic response. Stimulants may reduce fatigue or excessive sedation and improve concentration in patients receiving opioids for chronic pain. They also may have analgesic effects when combined with opioids. Potential adverse effects include appetite suppression, anxiety or agitation, confusion, tics, and addiction.⁶

Precautions. The muscle relaxant carisoprodol is associated with potential dependence and withdrawal. Cyclobenzaprine, another muscle relaxant, has a TCA-like structure and can be lethal in overdose. Baclofen can be useful for chronic pain related to spasticity, although psychotic depression and mania have been reported with abrupt withdrawal.⁶

Related resources

• American Academy of Pain Medicine. www.painmed.org/
• American Academy of Pain Management. www.aapainmanage.org
• Pain.com: continuing medical education for anesthesiology professionals. www.pain.com/index.cfm
• Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;13:345-56

Drug brand names

• Amitriptyline • Elavil
• Baclofen • Lioresal
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Carisoprodol • Soma
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Dihydrocodeine • Synalgos-DC
• Doxepin • Sinequan
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Hydrocodone • Vicodin, Lortab
• Imipramine • Tofranil
• Lithium • Eskalith CR, Lithobid
• Maprotiline • Ludiomil
• Meperidine • Demerol
• Methadone • Dolophine
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tizanidine • Zanaflex
• Tramadol • Ultram
• Trazodone • Desyrel
• Valproate • Depakote
• Venlafaxine • Effexor, Effexor XR

Disclosure

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

Depression can exacerbate cardiovascular disease (CVD), and CVD can exacerbate depression (Figure). Thus, effectively treating depression enhances heart disease treatment, particularly if psychiatrists and medical physicians collaborate in providing patient care.

This article describes a patient with risk factors for heart disease, illustrates the physiologic pathways that link depression and CVD, and offers clinical tips to help you improve outcomes for patients with both disorders.

Case report: Trying to ‘get going’

Mr. D, age 51, presents with vegetative symptoms and a personal and family history of CVD, depression, and substance abuse disorders. He was born in a small town in Kentucky and raised in Louisville’s poorest neighborhood. After his mother died at age 42 of “hardening of the arteries,” his father started drinking more, working less, and “never really got going again.”

Figure Neuroendocrine pathways by which depression may cause or promote CVD

Mr. D worked 20 years as a construction contractor, often running several work crews at once. At age 41, he slid into a depressive episode after his second divorce. He struggled with low energy, disturbed sleep, hopelessness, and increased smoking and drinking for 1 year, but he did not seek help.

Two years later, he suffered an inferior wall transmural myocardial infarction. His CVD risk factors included family history of early heart disease, smoking for 32 years, and elevated low-density lipoprotein (LDL) cholesterol. After subsequent episodes of unstable angina, stents were placed in two coronary arteries. Though his cardiologist cleared him to return to work, he felt able to work only part-time and erratically.

During a visit to their family doctor several years later, Mr. D’s wife suggested that her husband might be depressed. Reluctantly, Mr. D consulted a psychiatrist.

The psychiatrist diagnosed major depressive disorder and prescribed sertraline, 50 mg/d. Within 2 months, Mr. D’s symptoms had dropped by 50% on a symptom severity measure. He did not refill his prescription, however, because of concerns about sexual side effects. Two months later he was hospitalized for another episode of unstable angina. His depression had returned within 1 month of stopping sertraline.

The psychiatrist switched him to citalopram, 20 mg/d, and carefully monitored depressive symptoms, side effects, and medication adherence. Aside from talking with the psychiatrist for a half-hour in his family doctor’s office every few weeks, Mr. D refused to undergo psychotherapy. He eventually achieved depression remission with a combination of citalopram, 20 mg/d, and nefazodone, 200 mg/d.

Depression-CVD connection

As in Mr. D’s case, depression and CVD commonly occur together, often with serious consequences (Box). ^1-7 The association between depression and CVD is not limited to depression’s effect on existing disease, however. Depression often precedes coronary disease by about 30 years—suggesting possible cause and effect. Two systematic reviews^8,9 found that depression increased CVD risk by 64%.

Seven well-controlled studies^5-7,10-13 compared the relative effect of depression on the cardiovascular system with that of established CVD predictors. All seven found depression’s independent effect to be significant and comparable to or greater than that of ejection fraction, previous MI history, or number of vessels with >50% narrowing.

Comorbid depression and CVD usually persists months or years,¹⁴ and most studies indicate a dose-response relationship; the more severe the depression, the greater the risk for CVD to develop or progress.^8,15

The link between depression treatment and CVD risk has not been well-studied. The only randomized, controlled trial found that cognitive therapy for depression did not significantly reduce cardiac events among patients with known CVD.¹⁶

Possible mechanisms

Depression’s effect on CVD. How does depression affect CVD development and progression? Both behavioral and biological pathways may be involved.¹⁷ The behavioral pathway proposes that depression triggers behaviors—such as smoking, overeating, and sedentary lifestyles—that increase the risk of developing or worsening CVD. The biological pathway proposes that neuroendocrine changes during depression accelerate CVD development.

About one-half of persons with major depression exhibit hypothalamic-pituitary-adrenal (HPA) axis dysregulation, with excessive secretion of corticotropin releasing factor (CRF) and chronically elevated cortisol.¹⁸ This HPA dysregulation is related to defective negative feedback at the paraventricular nucleus of the hypothalamus. Chronic HPA axis dysregulation promotes vascular inflammation, and several studies have reported C-reactive protein elevation and cytokine changes in patients with major depression.^19,20

Major depression is also associated with excessive sympathetic and diminished parasym-pathetic nervous system activity, potentially contributing to hypertension, increased resting heart rate, decreased heart rate variability, and altered endothelial function.^2,21,22 Each of these factors facilitates arterial plaque formation.

Depression may also exacerbate chronic anxiety and other forms of distress. The combined effects of an overtaxed central nervous system, neuroendocrine dysregulation, and unhealthy behaviors may eventually overwhelm the cardiovascular system.

CVD’s effect on depression. How does CVD contribute to depression? The vascular depression hypothesis²³ proposes that diffuse heart and brain atherosclerosis restricts perfusion of limbic and cortical structures that regulate mood. A first depressive episode after acute MI or CABG probably represents exacerbation of cerebrovascular insufficiency that preceded the coronary event.

Table

Four keys to effectively treat depression in patients with heart disease

In practical terms, this means that pathways linking depression and heart disease include not only biological factors but also:

• psychological factors such as depression, anxiety, and chronic stress
• behavioral factors such as smoking, physical inactivity, and high-fat diet.

How to improve outcomes

Patients with CVD commonly do not receive effective depression treatment:

• Internists and family physicians give preferential attention to physical illness.
• Patients may have insufficient access to mental health specialists.
• Physicians do not adequately monitor depression treatment.
• Patients are reluctant to accept the stigma of mental illness.

By collaborating with primary care physicians, you can improve the likelihood that depression treatment will achieve remission and prevent relapse (Table).

Risk factors for CVD. Depression contributes to heart disease by exacerbating four major CVD risk factors—smoking, diabetes, obesity, and physical inactivity. By effectively treating depression, you may help patients avoid common depressive symptoms—such as overeating and sedentary behaviors—that are related to low energy or fatigue.

Educate middle-aged patients with depression about CVD’s associated risk. Prochaska’s “stages of change” (see Related resources) can help them stop smoking, lose weight, and exercise.

Access to cardiac care. Depressed patients may be less motivated than nondepressed patients to pursue cardiac care.²⁴ Therefore, you may need to:

• encourage your patients to take advantage of indicated state-of-the-art care, including stents, bypass surgery, and medications
• understand patients’ complex cardiac regimens and help them adhere when depression interferes with their motivation.

Effective depression treatment

Patient history. For depressed patients older than 40, take a careful inventory of CVD risk factors:

• family history of heart disease before age 60 for men and age 70 for women
• personal history of smoking, blood pressure >140/90 mm Hg, LDL cholesterol >100 mg/dL, type 2 diabetes, body mass index >30, or physical inactivity (<30 minutes of walking 3 days a week).

In general, the more risk factors, the greater the risk of CVD.

Antidepressant selection. Selective serotonin reuptake inhibitors (SSRIs) are safe and effective for treating major depression in CVD and congestive heart failure.²⁵ Venlafaxine at doses >300 mg/d may increase blood pressure, so use this drug with caution in depressed patients with hypertension.

No controlled clinical trials have gauged the safety and efficacy of bupropion or mirtazapine in patients with CVD.

Tricyclic antidepressants are contraindicated for 6 months post-MI because they may contribute to arrhythmias. Avoid using them in depressed patients with CVD or conduction defects because of their quinidine-like effects on conduction.

Cardiac medications. Contrary to folk wisdom, beta blockers do not cause depression.²⁶ Whether or not a patient is depressed, our primary care and cardiology colleagues can use beta blockers to help regulate the peripheral autonomic nervous system, reducing high blood pressure and the risk of arrhythmias.

SSRIs may increase blood levels of beta blockers, warfarin, and other cardiac medications via cytochrome P-450 isoenzyme inhibition. Make sure warfarin levels and other cardiac drug effects are well monitored when you adjust psychotropic dosages.

Divalproex and SSRIs also may reduce platelet aggregation. Patients who are receiving concomitant aspirin or warfarin may bruise or bleed easily and require dosage reductions or medication changes.

Psychotherapy. All patients with major or minor depression and CVD are considered high-risk and are candidates for a trial of brief psychotherapy. Therapeutic goals are to achieve full remission of depressive symptoms as rapidly as possible, prevent relapse, and maximize adherence to cardiac and depression drug regimens.

Collaborate closely with the cardiologist or primary care physician during the patient’s depressive episode and occasionally during maintenance treatment. Discuss or share notes on the patient’s depressive and cardiac disorders, medication management, symptom monitoring, and behavior changes needed to reduce cardiac risk.

With your added support, patients with depression and CVD are more likely to adhere to antidepressant medications and achieve symptom remission.

Related resources

• National Institute of Mental Health. Depression and heart disease. www.nimh.nih.gov/publicat/depheart.cfm.
• Dewan NA, Suresh DP, Blomkalns A. Selecting safe psychotropics for post-MI patients. Current Psychiatry. 2003;2(3):15-21.
• Prochaska JO, Norcross JC, DiClemente CC. Changing for good. New York: Avon, 1994.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Wulsin is a consultant to Pfizer Inc. and Janssen Pharmaceutica.

Dr. Vieweg is a speaker for Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Depression can exacerbate cardiovascular disease (CVD), and CVD can exacerbate depression (Figure). Thus, effectively treating depression enhances heart disease treatment, particularly if psychiatrists and medical physicians collaborate in providing patient care.

This article describes a patient with risk factors for heart disease, illustrates the physiologic pathways that link depression and CVD, and offers clinical tips to help you improve outcomes for patients with both disorders.

Case report: Trying to ‘get going’

Mr. D, age 51, presents with vegetative symptoms and a personal and family history of CVD, depression, and substance abuse disorders. He was born in a small town in Kentucky and raised in Louisville’s poorest neighborhood. After his mother died at age 42 of “hardening of the arteries,” his father started drinking more, working less, and “never really got going again.”

Figure Neuroendocrine pathways by which depression may cause or promote CVD

Mr. D worked 20 years as a construction contractor, often running several work crews at once. At age 41, he slid into a depressive episode after his second divorce. He struggled with low energy, disturbed sleep, hopelessness, and increased smoking and drinking for 1 year, but he did not seek help.

Two years later, he suffered an inferior wall transmural myocardial infarction. His CVD risk factors included family history of early heart disease, smoking for 32 years, and elevated low-density lipoprotein (LDL) cholesterol. After subsequent episodes of unstable angina, stents were placed in two coronary arteries. Though his cardiologist cleared him to return to work, he felt able to work only part-time and erratically.

During a visit to their family doctor several years later, Mr. D’s wife suggested that her husband might be depressed. Reluctantly, Mr. D consulted a psychiatrist.

The psychiatrist diagnosed major depressive disorder and prescribed sertraline, 50 mg/d. Within 2 months, Mr. D’s symptoms had dropped by 50% on a symptom severity measure. He did not refill his prescription, however, because of concerns about sexual side effects. Two months later he was hospitalized for another episode of unstable angina. His depression had returned within 1 month of stopping sertraline.

The psychiatrist switched him to citalopram, 20 mg/d, and carefully monitored depressive symptoms, side effects, and medication adherence. Aside from talking with the psychiatrist for a half-hour in his family doctor’s office every few weeks, Mr. D refused to undergo psychotherapy. He eventually achieved depression remission with a combination of citalopram, 20 mg/d, and nefazodone, 200 mg/d.

Depression-CVD connection

As in Mr. D’s case, depression and CVD commonly occur together, often with serious consequences (Box). ^1-7 The association between depression and CVD is not limited to depression’s effect on existing disease, however. Depression often precedes coronary disease by about 30 years—suggesting possible cause and effect. Two systematic reviews^8,9 found that depression increased CVD risk by 64%.

Seven well-controlled studies^5-7,10-13 compared the relative effect of depression on the cardiovascular system with that of established CVD predictors. All seven found depression’s independent effect to be significant and comparable to or greater than that of ejection fraction, previous MI history, or number of vessels with >50% narrowing.

Comorbid depression and CVD usually persists months or years,¹⁴ and most studies indicate a dose-response relationship; the more severe the depression, the greater the risk for CVD to develop or progress.^8,15

The link between depression treatment and CVD risk has not been well-studied. The only randomized, controlled trial found that cognitive therapy for depression did not significantly reduce cardiac events among patients with known CVD.¹⁶

Possible mechanisms

Depression’s effect on CVD. How does depression affect CVD development and progression? Both behavioral and biological pathways may be involved.¹⁷ The behavioral pathway proposes that depression triggers behaviors—such as smoking, overeating, and sedentary lifestyles—that increase the risk of developing or worsening CVD. The biological pathway proposes that neuroendocrine changes during depression accelerate CVD development.

About one-half of persons with major depression exhibit hypothalamic-pituitary-adrenal (HPA) axis dysregulation, with excessive secretion of corticotropin releasing factor (CRF) and chronically elevated cortisol.¹⁸ This HPA dysregulation is related to defective negative feedback at the paraventricular nucleus of the hypothalamus. Chronic HPA axis dysregulation promotes vascular inflammation, and several studies have reported C-reactive protein elevation and cytokine changes in patients with major depression.^19,20

Major depression is also associated with excessive sympathetic and diminished parasym-pathetic nervous system activity, potentially contributing to hypertension, increased resting heart rate, decreased heart rate variability, and altered endothelial function.^2,21,22 Each of these factors facilitates arterial plaque formation.

Depression may also exacerbate chronic anxiety and other forms of distress. The combined effects of an overtaxed central nervous system, neuroendocrine dysregulation, and unhealthy behaviors may eventually overwhelm the cardiovascular system.

CVD’s effect on depression. How does CVD contribute to depression? The vascular depression hypothesis²³ proposes that diffuse heart and brain atherosclerosis restricts perfusion of limbic and cortical structures that regulate mood. A first depressive episode after acute MI or CABG probably represents exacerbation of cerebrovascular insufficiency that preceded the coronary event.

Table

Four keys to effectively treat depression in patients with heart disease

In practical terms, this means that pathways linking depression and heart disease include not only biological factors but also:

• psychological factors such as depression, anxiety, and chronic stress
• behavioral factors such as smoking, physical inactivity, and high-fat diet.

How to improve outcomes

Patients with CVD commonly do not receive effective depression treatment:

• Internists and family physicians give preferential attention to physical illness.
• Patients may have insufficient access to mental health specialists.
• Physicians do not adequately monitor depression treatment.
• Patients are reluctant to accept the stigma of mental illness.

By collaborating with primary care physicians, you can improve the likelihood that depression treatment will achieve remission and prevent relapse (Table).

Risk factors for CVD. Depression contributes to heart disease by exacerbating four major CVD risk factors—smoking, diabetes, obesity, and physical inactivity. By effectively treating depression, you may help patients avoid common depressive symptoms—such as overeating and sedentary behaviors—that are related to low energy or fatigue.

Educate middle-aged patients with depression about CVD’s associated risk. Prochaska’s “stages of change” (see Related resources) can help them stop smoking, lose weight, and exercise.

Access to cardiac care. Depressed patients may be less motivated than nondepressed patients to pursue cardiac care.²⁴ Therefore, you may need to:

• encourage your patients to take advantage of indicated state-of-the-art care, including stents, bypass surgery, and medications
• understand patients’ complex cardiac regimens and help them adhere when depression interferes with their motivation.

Effective depression treatment

Patient history. For depressed patients older than 40, take a careful inventory of CVD risk factors:

• family history of heart disease before age 60 for men and age 70 for women
• personal history of smoking, blood pressure >140/90 mm Hg, LDL cholesterol >100 mg/dL, type 2 diabetes, body mass index >30, or physical inactivity (<30 minutes of walking 3 days a week).

In general, the more risk factors, the greater the risk of CVD.

Antidepressant selection. Selective serotonin reuptake inhibitors (SSRIs) are safe and effective for treating major depression in CVD and congestive heart failure.²⁵ Venlafaxine at doses >300 mg/d may increase blood pressure, so use this drug with caution in depressed patients with hypertension.

No controlled clinical trials have gauged the safety and efficacy of bupropion or mirtazapine in patients with CVD.

Tricyclic antidepressants are contraindicated for 6 months post-MI because they may contribute to arrhythmias. Avoid using them in depressed patients with CVD or conduction defects because of their quinidine-like effects on conduction.

Cardiac medications. Contrary to folk wisdom, beta blockers do not cause depression.²⁶ Whether or not a patient is depressed, our primary care and cardiology colleagues can use beta blockers to help regulate the peripheral autonomic nervous system, reducing high blood pressure and the risk of arrhythmias.

SSRIs may increase blood levels of beta blockers, warfarin, and other cardiac medications via cytochrome P-450 isoenzyme inhibition. Make sure warfarin levels and other cardiac drug effects are well monitored when you adjust psychotropic dosages.

Divalproex and SSRIs also may reduce platelet aggregation. Patients who are receiving concomitant aspirin or warfarin may bruise or bleed easily and require dosage reductions or medication changes.

Psychotherapy. All patients with major or minor depression and CVD are considered high-risk and are candidates for a trial of brief psychotherapy. Therapeutic goals are to achieve full remission of depressive symptoms as rapidly as possible, prevent relapse, and maximize adherence to cardiac and depression drug regimens.

Collaborate closely with the cardiologist or primary care physician during the patient’s depressive episode and occasionally during maintenance treatment. Discuss or share notes on the patient’s depressive and cardiac disorders, medication management, symptom monitoring, and behavior changes needed to reduce cardiac risk.

With your added support, patients with depression and CVD are more likely to adhere to antidepressant medications and achieve symptom remission.

Related resources

• National Institute of Mental Health. Depression and heart disease. www.nimh.nih.gov/publicat/depheart.cfm.
• Dewan NA, Suresh DP, Blomkalns A. Selecting safe psychotropics for post-MI patients. Current Psychiatry. 2003;2(3):15-21.
• Prochaska JO, Norcross JC, DiClemente CC. Changing for good. New York: Avon, 1994.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Wulsin is a consultant to Pfizer Inc. and Janssen Pharmaceutica.

Dr. Vieweg is a speaker for Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

Depression can exacerbate cardiovascular disease (CVD), and CVD can exacerbate depression (Figure). Thus, effectively treating depression enhances heart disease treatment, particularly if psychiatrists and medical physicians collaborate in providing patient care.

This article describes a patient with risk factors for heart disease, illustrates the physiologic pathways that link depression and CVD, and offers clinical tips to help you improve outcomes for patients with both disorders.

Case report: Trying to ‘get going’

Mr. D, age 51, presents with vegetative symptoms and a personal and family history of CVD, depression, and substance abuse disorders. He was born in a small town in Kentucky and raised in Louisville’s poorest neighborhood. After his mother died at age 42 of “hardening of the arteries,” his father started drinking more, working less, and “never really got going again.”

Figure Neuroendocrine pathways by which depression may cause or promote CVD

Mr. D worked 20 years as a construction contractor, often running several work crews at once. At age 41, he slid into a depressive episode after his second divorce. He struggled with low energy, disturbed sleep, hopelessness, and increased smoking and drinking for 1 year, but he did not seek help.

Two years later, he suffered an inferior wall transmural myocardial infarction. His CVD risk factors included family history of early heart disease, smoking for 32 years, and elevated low-density lipoprotein (LDL) cholesterol. After subsequent episodes of unstable angina, stents were placed in two coronary arteries. Though his cardiologist cleared him to return to work, he felt able to work only part-time and erratically.

During a visit to their family doctor several years later, Mr. D’s wife suggested that her husband might be depressed. Reluctantly, Mr. D consulted a psychiatrist.

The psychiatrist diagnosed major depressive disorder and prescribed sertraline, 50 mg/d. Within 2 months, Mr. D’s symptoms had dropped by 50% on a symptom severity measure. He did not refill his prescription, however, because of concerns about sexual side effects. Two months later he was hospitalized for another episode of unstable angina. His depression had returned within 1 month of stopping sertraline.

The psychiatrist switched him to citalopram, 20 mg/d, and carefully monitored depressive symptoms, side effects, and medication adherence. Aside from talking with the psychiatrist for a half-hour in his family doctor’s office every few weeks, Mr. D refused to undergo psychotherapy. He eventually achieved depression remission with a combination of citalopram, 20 mg/d, and nefazodone, 200 mg/d.

Depression-CVD connection

As in Mr. D’s case, depression and CVD commonly occur together, often with serious consequences (Box). ^1-7 The association between depression and CVD is not limited to depression’s effect on existing disease, however. Depression often precedes coronary disease by about 30 years—suggesting possible cause and effect. Two systematic reviews^8,9 found that depression increased CVD risk by 64%.

Seven well-controlled studies^5-7,10-13 compared the relative effect of depression on the cardiovascular system with that of established CVD predictors. All seven found depression’s independent effect to be significant and comparable to or greater than that of ejection fraction, previous MI history, or number of vessels with >50% narrowing.

Comorbid depression and CVD usually persists months or years,¹⁴ and most studies indicate a dose-response relationship; the more severe the depression, the greater the risk for CVD to develop or progress.^8,15

The link between depression treatment and CVD risk has not been well-studied. The only randomized, controlled trial found that cognitive therapy for depression did not significantly reduce cardiac events among patients with known CVD.¹⁶

Possible mechanisms

Depression’s effect on CVD. How does depression affect CVD development and progression? Both behavioral and biological pathways may be involved.¹⁷ The behavioral pathway proposes that depression triggers behaviors—such as smoking, overeating, and sedentary lifestyles—that increase the risk of developing or worsening CVD. The biological pathway proposes that neuroendocrine changes during depression accelerate CVD development.

About one-half of persons with major depression exhibit hypothalamic-pituitary-adrenal (HPA) axis dysregulation, with excessive secretion of corticotropin releasing factor (CRF) and chronically elevated cortisol.¹⁸ This HPA dysregulation is related to defective negative feedback at the paraventricular nucleus of the hypothalamus. Chronic HPA axis dysregulation promotes vascular inflammation, and several studies have reported C-reactive protein elevation and cytokine changes in patients with major depression.^19,20

Major depression is also associated with excessive sympathetic and diminished parasym-pathetic nervous system activity, potentially contributing to hypertension, increased resting heart rate, decreased heart rate variability, and altered endothelial function.^2,21,22 Each of these factors facilitates arterial plaque formation.

Depression may also exacerbate chronic anxiety and other forms of distress. The combined effects of an overtaxed central nervous system, neuroendocrine dysregulation, and unhealthy behaviors may eventually overwhelm the cardiovascular system.

CVD’s effect on depression. How does CVD contribute to depression? The vascular depression hypothesis²³ proposes that diffuse heart and brain atherosclerosis restricts perfusion of limbic and cortical structures that regulate mood. A first depressive episode after acute MI or CABG probably represents exacerbation of cerebrovascular insufficiency that preceded the coronary event.

Table

Four keys to effectively treat depression in patients with heart disease

In practical terms, this means that pathways linking depression and heart disease include not only biological factors but also:

• psychological factors such as depression, anxiety, and chronic stress
• behavioral factors such as smoking, physical inactivity, and high-fat diet.

How to improve outcomes

Patients with CVD commonly do not receive effective depression treatment:

• Internists and family physicians give preferential attention to physical illness.
• Patients may have insufficient access to mental health specialists.
• Physicians do not adequately monitor depression treatment.
• Patients are reluctant to accept the stigma of mental illness.

By collaborating with primary care physicians, you can improve the likelihood that depression treatment will achieve remission and prevent relapse (Table).

Risk factors for CVD. Depression contributes to heart disease by exacerbating four major CVD risk factors—smoking, diabetes, obesity, and physical inactivity. By effectively treating depression, you may help patients avoid common depressive symptoms—such as overeating and sedentary behaviors—that are related to low energy or fatigue.

Educate middle-aged patients with depression about CVD’s associated risk. Prochaska’s “stages of change” (see Related resources) can help them stop smoking, lose weight, and exercise.

Access to cardiac care. Depressed patients may be less motivated than nondepressed patients to pursue cardiac care.²⁴ Therefore, you may need to:

• encourage your patients to take advantage of indicated state-of-the-art care, including stents, bypass surgery, and medications
• understand patients’ complex cardiac regimens and help them adhere when depression interferes with their motivation.

Effective depression treatment

Patient history. For depressed patients older than 40, take a careful inventory of CVD risk factors:

• family history of heart disease before age 60 for men and age 70 for women
• personal history of smoking, blood pressure >140/90 mm Hg, LDL cholesterol >100 mg/dL, type 2 diabetes, body mass index >30, or physical inactivity (<30 minutes of walking 3 days a week).

In general, the more risk factors, the greater the risk of CVD.

Antidepressant selection. Selective serotonin reuptake inhibitors (SSRIs) are safe and effective for treating major depression in CVD and congestive heart failure.²⁵ Venlafaxine at doses >300 mg/d may increase blood pressure, so use this drug with caution in depressed patients with hypertension.

No controlled clinical trials have gauged the safety and efficacy of bupropion or mirtazapine in patients with CVD.

Tricyclic antidepressants are contraindicated for 6 months post-MI because they may contribute to arrhythmias. Avoid using them in depressed patients with CVD or conduction defects because of their quinidine-like effects on conduction.

Cardiac medications. Contrary to folk wisdom, beta blockers do not cause depression.²⁶ Whether or not a patient is depressed, our primary care and cardiology colleagues can use beta blockers to help regulate the peripheral autonomic nervous system, reducing high blood pressure and the risk of arrhythmias.

SSRIs may increase blood levels of beta blockers, warfarin, and other cardiac medications via cytochrome P-450 isoenzyme inhibition. Make sure warfarin levels and other cardiac drug effects are well monitored when you adjust psychotropic dosages.

Divalproex and SSRIs also may reduce platelet aggregation. Patients who are receiving concomitant aspirin or warfarin may bruise or bleed easily and require dosage reductions or medication changes.

Psychotherapy. All patients with major or minor depression and CVD are considered high-risk and are candidates for a trial of brief psychotherapy. Therapeutic goals are to achieve full remission of depressive symptoms as rapidly as possible, prevent relapse, and maximize adherence to cardiac and depression drug regimens.

Collaborate closely with the cardiologist or primary care physician during the patient’s depressive episode and occasionally during maintenance treatment. Discuss or share notes on the patient’s depressive and cardiac disorders, medication management, symptom monitoring, and behavior changes needed to reduce cardiac risk.

With your added support, patients with depression and CVD are more likely to adhere to antidepressant medications and achieve symptom remission.

Related resources

• National Institute of Mental Health. Depression and heart disease. www.nimh.nih.gov/publicat/depheart.cfm.
• Dewan NA, Suresh DP, Blomkalns A. Selecting safe psychotropics for post-MI patients. Current Psychiatry. 2003;2(3):15-21.
• Prochaska JO, Norcross JC, DiClemente CC. Changing for good. New York: Avon, 1994.

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Paroxetine • Paxil
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Wulsin is a consultant to Pfizer Inc. and Janssen Pharmaceutica.

Dr. Vieweg is a speaker for Janssen Pharmaceutica, Eli Lilly and Co., Pfizer Inc., Wyeth Pharmaceuticals, Forest Pharmaceuticals, and GlaxoSmithKline.

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

HISTORY: Treatment-refractory depression

Mr. S, age 78, has a history of depression that has not responded to selective serotonin reuptake inhibitors and electroconvulsive therapy (ECT).

According to his niece, Mr. S had become withdrawn, suspicious, and forgetful. Several times over the past year, police found him wandering the streets and brought him to the community hospital’s emergency room.

During one emergency room visit, he complained of decreased appetite, poor sleep, and depressed mood. He was subsequently admitted to the psychiatric unit, where he was treated with ECT and discharged on citalopram, 20 mg/d. His symptoms did not improve and he became ataxic and incontinent of urine.

Mr. S’ family placed him in a nursing home, where he became increasingly paranoid. The attending physician prescribed risperidone, 3 mg/d, with no effect. He was then transferred to our psychiatric facility.

At admission, Mr. S told us that a group of men disguised in toupees and mustaches were out to kill him. He said these men had recently killed his niece—with whom he had just spoken on the phone and had seen at the hospital. He suspected that these men were after his money, hired a woman to impersonate his niece and spy on him, and planned to bury his body and his niece’s in a remote place.

On evaluation, Mr. S was suspicious, guarded, and uncooperative, and often ended conversations abruptly. He denied auditory and visual hallucinations, was not suicidal or homicidal, and denied abusing drugs or alcohol. He said constant fear of his imminent murder left him feeling depressed.

Physical and neurologic exams were unremarkable except for mild ataxia. Mr. S’ Folstein Mini-Mental State Examination score was 19/30, indicating moderate cognitive impairment.

Mr. S’ history and behavior suggest depression with psychotic features. Do we have enough information for a diagnosis?

Dr. Greenberg’s and Tampi’s observations

Mr. S is displaying mood symptoms consistent with his prior diagnosis of depression, but with new-onset psychosis as well.

Because of Mr. S’ neurobiologic symptoms, it is improper to diagnose depression with psychotic features without first performing a full medical and neurologic workup. The differential diagnosis needs to include medical and neurologic diagnoses, including:

• delirium secondary to urinary tract infection
• Alzheimer’s and/or vascular dementia
• normal-pressure hydrocephalus
• substance abuse.

A complete dementia and delirium workup and detailed medical history are imperative.

FURTHER HISTORY: Risky behavior

Further history reveals that Mr. S had been having sexual intercourse with prostitutes since his early teens and that this habit continued into his 70s. He had been diagnosed with syphilis in his teens and again in his 50s. Both times he refused to complete the recommended penicillin regimen because he was embarrassed by the diagnosis and had falsely believed that a single penicillin injection would cure him.

Lab tests showed a white blood cell count of 3.5 and a weakly reactive serum venereal disease research laboratory (VDRL) reading.

Box 1

Could Mr. S’ syphilis—inadequately treated in his youth—be causing his depression and paranoia decades later? If so, how would you confirm this finding?

Dr. Greenberg’s and Tampi’s observations

Mr. S has a longstanding history of syphilis secondary to high-risk sexual activity. This, combined with the lab findings and his worsening depression and paranoia, points to possible neurosyphilis.

Syphilis, caused by the spirochete Treponema pallidum., can traverse mucous membranes and abraded skin. Transmission is most common during sexual activity but also occurs through blood transfusions and nonsexual lesion contact and from mother to fetus.

Box 2

Because syphilis and its psychiatric effects are relatively uncommon (Box 1), many psychiatrists do not consider neurosyphilis in high-risk patients who present with depression, dementia, or psychosis (Box 2).

HOW SYPHILIS BECOMES NEUROSYPHILIS

Primary syphilis incubates for 10 to 90 days following infection. After this period, an infectious chancre appears along with regional adenopathy. If untreated, the chancre will disappear but the infection will progress.

Secondary syphilis is characterized by skin manifestations and occasionally affects the joints, eyes, bones, kidneys, liver, and CNS. Common effects include condylomata—highly infectious warty lesions—and a diffuse maculopapular rash on the palms and soles. These lesions disappear if left untreated, but most patients then either enter syphilis’ latent stage or experience a potentially fatal relapse of secondary syphilis.⁵

Latent syphilis usually remains latent or resolves, but about one-third of patients with latent syphilis slowly progress to tertiary syphilis. Neurosyphilis, one of the main forms of tertiary syphilis, can surface 5 to 35 years after an untreated primary infection.⁷

There are four categories of neurosyphilis:

• General paresis results in dementia, changes in personality, transient hemiparesis, depression, and psychosis.
• Tabes dorsalis degenerates the posterior columns and dorsal root ganglia of the spinal cord. This results in ataxia, parasthesias, decreased proprioception and vibratory sense, Argyll Robertson pupil (an optical disorder in which the pupil does not react normally to light), neurogenic bladder, and sharp shooting pains throughout the body.
• Meningovascular neurosyphilis can result in cranial nerve abnormalities, symptoms of meningitis, and cerebral infarctions.
• Asymptomatic but with CSF positive for syphilis.

Neurosyphilis is fatal if untreated, and treatment usually does not eliminate symptoms but prevents further progression. Approximately 8% of patients with untreated primary syphilis develop neurosyphilis.^5,7

Standard nontreponemal tests, such as the VDRL or rapid plasmin reagin, can be used to screen for syphilis. Because these tests often produce false positives, confirm positive results with a syphilis-specific test, such as the fluorescent treponemal antibody absorption (FTA-ABS) test, microhemagglutination assay for antibodies to T pallidum., and the T pallidum. hemagglutination assay.

If neurosyphilis is suspected, CSF testing is strongly recommended. Diagnostic findings include elevated white blood cell and protein counts and a positive VDRL. If the CSF is negative, refer the patient for treatment anyway because false negatives are common. Patients with consistent neurologic symptoms, positive VDRL and/or FTA-ABS, and negative CSF are diagnosed with neurosyphilis and warrant treatment.⁷

How would you manage Mr. S’ psychiatric symptoms concomitant with medical treatment of late-stage syphilis?

Dr. Greenberg’s and Tampi’s observations

Although no specific guidelines exist for treating psychosis secondary to neurosyphilis, atypical antipsychotics remain the first-line treatment. Atypicals do not interact significantly with penicillin and can be given safely with syphilis treatment. Atypicals also are better tolerated than typical antipsychotics and produce fewer extrapyramidal symptoms, which are common among older patients and those with neurologic diseases.

Screening for syphilis. Every patient with a history of high-risk sexual behavior who presents with new-onset dementia or psychosis should be screened for syphilis. Sexual history can be difficult to obtain from some patients and family members, so communication between providers becomes crucial. Obtain lab test results from other care team members to monitor compliance, and coordinate patient education with other doctors on safe sexual practices.

TREATMENT: Taking his medicine

Mr. S refused further testing and emergency conservatorship was sought. Citalopram was discontinued and risperidone was gradually increased to 6 mg at bedtime. He remained paranoid and delusional.

A brain MRI showed chronic ischemic small-vessel disease. HIV testing was negative, and serum FTA-ABS was reactive. CSF showed elevated protein and white blood cell count with a nonreactive VDRL and a reactive FTA-ABS. A diagnosis of neurosyphilis was made, and treatment was initiated with aqueous crystalline penicillin G, 4 million units every 4 hours for 2 weeks.

Mr. S was discharged back to the nursing home where his penicillin injections were continued. His paranoia diminished slightly but he remained ataxic, incontinent, and confused. He was discharged from the nursing home but needed confirmative HIV screening and repeated CSF testing to determine if syphilis treatment was effective.

Six months after treatment, Mr. S’ niece reports that his paranoia has decreased. He has not needed additional psychiatric hospitalizations.

Related resources

• Merck Manual. www.merck.com. Search: “syphilis”
• U.S. Centers for Disease Control and Prevention—Syphilis elimination: History in the making. www.cdc.gov. Click on “Health Topics A-Z,” then click on “S” and find “syphilis.”
• National Institute of Allergy and Infectious Disease. www.niaid.nih.gov. Search: “syphilis”

Drug brand names

• Citalopram • Celexa
• Risperidone • Risperdal

Disclosure

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

HISTORY: Treatment-refractory depression

Mr. S, age 78, has a history of depression that has not responded to selective serotonin reuptake inhibitors and electroconvulsive therapy (ECT).

According to his niece, Mr. S had become withdrawn, suspicious, and forgetful. Several times over the past year, police found him wandering the streets and brought him to the community hospital’s emergency room.

During one emergency room visit, he complained of decreased appetite, poor sleep, and depressed mood. He was subsequently admitted to the psychiatric unit, where he was treated with ECT and discharged on citalopram, 20 mg/d. His symptoms did not improve and he became ataxic and incontinent of urine.

Mr. S’ family placed him in a nursing home, where he became increasingly paranoid. The attending physician prescribed risperidone, 3 mg/d, with no effect. He was then transferred to our psychiatric facility.

At admission, Mr. S told us that a group of men disguised in toupees and mustaches were out to kill him. He said these men had recently killed his niece—with whom he had just spoken on the phone and had seen at the hospital. He suspected that these men were after his money, hired a woman to impersonate his niece and spy on him, and planned to bury his body and his niece’s in a remote place.

On evaluation, Mr. S was suspicious, guarded, and uncooperative, and often ended conversations abruptly. He denied auditory and visual hallucinations, was not suicidal or homicidal, and denied abusing drugs or alcohol. He said constant fear of his imminent murder left him feeling depressed.

Physical and neurologic exams were unremarkable except for mild ataxia. Mr. S’ Folstein Mini-Mental State Examination score was 19/30, indicating moderate cognitive impairment.

Mr. S’ history and behavior suggest depression with psychotic features. Do we have enough information for a diagnosis?

Dr. Greenberg’s and Tampi’s observations

Mr. S is displaying mood symptoms consistent with his prior diagnosis of depression, but with new-onset psychosis as well.

Because of Mr. S’ neurobiologic symptoms, it is improper to diagnose depression with psychotic features without first performing a full medical and neurologic workup. The differential diagnosis needs to include medical and neurologic diagnoses, including:

• delirium secondary to urinary tract infection
• Alzheimer’s and/or vascular dementia
• normal-pressure hydrocephalus
• substance abuse.

A complete dementia and delirium workup and detailed medical history are imperative.

FURTHER HISTORY: Risky behavior

Further history reveals that Mr. S had been having sexual intercourse with prostitutes since his early teens and that this habit continued into his 70s. He had been diagnosed with syphilis in his teens and again in his 50s. Both times he refused to complete the recommended penicillin regimen because he was embarrassed by the diagnosis and had falsely believed that a single penicillin injection would cure him.

Lab tests showed a white blood cell count of 3.5 and a weakly reactive serum venereal disease research laboratory (VDRL) reading.

Box 1

Could Mr. S’ syphilis—inadequately treated in his youth—be causing his depression and paranoia decades later? If so, how would you confirm this finding?

Dr. Greenberg’s and Tampi’s observations

Mr. S has a longstanding history of syphilis secondary to high-risk sexual activity. This, combined with the lab findings and his worsening depression and paranoia, points to possible neurosyphilis.

Syphilis, caused by the spirochete Treponema pallidum., can traverse mucous membranes and abraded skin. Transmission is most common during sexual activity but also occurs through blood transfusions and nonsexual lesion contact and from mother to fetus.

Box 2

Because syphilis and its psychiatric effects are relatively uncommon (Box 1), many psychiatrists do not consider neurosyphilis in high-risk patients who present with depression, dementia, or psychosis (Box 2).

HOW SYPHILIS BECOMES NEUROSYPHILIS

Primary syphilis incubates for 10 to 90 days following infection. After this period, an infectious chancre appears along with regional adenopathy. If untreated, the chancre will disappear but the infection will progress.

Secondary syphilis is characterized by skin manifestations and occasionally affects the joints, eyes, bones, kidneys, liver, and CNS. Common effects include condylomata—highly infectious warty lesions—and a diffuse maculopapular rash on the palms and soles. These lesions disappear if left untreated, but most patients then either enter syphilis’ latent stage or experience a potentially fatal relapse of secondary syphilis.⁵

Latent syphilis usually remains latent or resolves, but about one-third of patients with latent syphilis slowly progress to tertiary syphilis. Neurosyphilis, one of the main forms of tertiary syphilis, can surface 5 to 35 years after an untreated primary infection.⁷

There are four categories of neurosyphilis:

• General paresis results in dementia, changes in personality, transient hemiparesis, depression, and psychosis.
• Tabes dorsalis degenerates the posterior columns and dorsal root ganglia of the spinal cord. This results in ataxia, parasthesias, decreased proprioception and vibratory sense, Argyll Robertson pupil (an optical disorder in which the pupil does not react normally to light), neurogenic bladder, and sharp shooting pains throughout the body.
• Meningovascular neurosyphilis can result in cranial nerve abnormalities, symptoms of meningitis, and cerebral infarctions.
• Asymptomatic but with CSF positive for syphilis.

Neurosyphilis is fatal if untreated, and treatment usually does not eliminate symptoms but prevents further progression. Approximately 8% of patients with untreated primary syphilis develop neurosyphilis.^5,7

Standard nontreponemal tests, such as the VDRL or rapid plasmin reagin, can be used to screen for syphilis. Because these tests often produce false positives, confirm positive results with a syphilis-specific test, such as the fluorescent treponemal antibody absorption (FTA-ABS) test, microhemagglutination assay for antibodies to T pallidum., and the T pallidum. hemagglutination assay.

If neurosyphilis is suspected, CSF testing is strongly recommended. Diagnostic findings include elevated white blood cell and protein counts and a positive VDRL. If the CSF is negative, refer the patient for treatment anyway because false negatives are common. Patients with consistent neurologic symptoms, positive VDRL and/or FTA-ABS, and negative CSF are diagnosed with neurosyphilis and warrant treatment.⁷

How would you manage Mr. S’ psychiatric symptoms concomitant with medical treatment of late-stage syphilis?

Dr. Greenberg’s and Tampi’s observations

Although no specific guidelines exist for treating psychosis secondary to neurosyphilis, atypical antipsychotics remain the first-line treatment. Atypicals do not interact significantly with penicillin and can be given safely with syphilis treatment. Atypicals also are better tolerated than typical antipsychotics and produce fewer extrapyramidal symptoms, which are common among older patients and those with neurologic diseases.

Screening for syphilis. Every patient with a history of high-risk sexual behavior who presents with new-onset dementia or psychosis should be screened for syphilis. Sexual history can be difficult to obtain from some patients and family members, so communication between providers becomes crucial. Obtain lab test results from other care team members to monitor compliance, and coordinate patient education with other doctors on safe sexual practices.

TREATMENT: Taking his medicine

Mr. S refused further testing and emergency conservatorship was sought. Citalopram was discontinued and risperidone was gradually increased to 6 mg at bedtime. He remained paranoid and delusional.

A brain MRI showed chronic ischemic small-vessel disease. HIV testing was negative, and serum FTA-ABS was reactive. CSF showed elevated protein and white blood cell count with a nonreactive VDRL and a reactive FTA-ABS. A diagnosis of neurosyphilis was made, and treatment was initiated with aqueous crystalline penicillin G, 4 million units every 4 hours for 2 weeks.

Mr. S was discharged back to the nursing home where his penicillin injections were continued. His paranoia diminished slightly but he remained ataxic, incontinent, and confused. He was discharged from the nursing home but needed confirmative HIV screening and repeated CSF testing to determine if syphilis treatment was effective.

Six months after treatment, Mr. S’ niece reports that his paranoia has decreased. He has not needed additional psychiatric hospitalizations.

Related resources

• Merck Manual. www.merck.com. Search: “syphilis”
• U.S. Centers for Disease Control and Prevention—Syphilis elimination: History in the making. www.cdc.gov. Click on “Health Topics A-Z,” then click on “S” and find “syphilis.”
• National Institute of Allergy and Infectious Disease. www.niaid.nih.gov. Search: “syphilis”

Drug brand names

• Citalopram • Celexa
• Risperidone • Risperdal

Disclosure

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

HISTORY: Treatment-refractory depression

Mr. S, age 78, has a history of depression that has not responded to selective serotonin reuptake inhibitors and electroconvulsive therapy (ECT).

According to his niece, Mr. S had become withdrawn, suspicious, and forgetful. Several times over the past year, police found him wandering the streets and brought him to the community hospital’s emergency room.

During one emergency room visit, he complained of decreased appetite, poor sleep, and depressed mood. He was subsequently admitted to the psychiatric unit, where he was treated with ECT and discharged on citalopram, 20 mg/d. His symptoms did not improve and he became ataxic and incontinent of urine.

Mr. S’ family placed him in a nursing home, where he became increasingly paranoid. The attending physician prescribed risperidone, 3 mg/d, with no effect. He was then transferred to our psychiatric facility.

At admission, Mr. S told us that a group of men disguised in toupees and mustaches were out to kill him. He said these men had recently killed his niece—with whom he had just spoken on the phone and had seen at the hospital. He suspected that these men were after his money, hired a woman to impersonate his niece and spy on him, and planned to bury his body and his niece’s in a remote place.

On evaluation, Mr. S was suspicious, guarded, and uncooperative, and often ended conversations abruptly. He denied auditory and visual hallucinations, was not suicidal or homicidal, and denied abusing drugs or alcohol. He said constant fear of his imminent murder left him feeling depressed.

Physical and neurologic exams were unremarkable except for mild ataxia. Mr. S’ Folstein Mini-Mental State Examination score was 19/30, indicating moderate cognitive impairment.

Mr. S’ history and behavior suggest depression with psychotic features. Do we have enough information for a diagnosis?

Dr. Greenberg’s and Tampi’s observations

Mr. S is displaying mood symptoms consistent with his prior diagnosis of depression, but with new-onset psychosis as well.

Because of Mr. S’ neurobiologic symptoms, it is improper to diagnose depression with psychotic features without first performing a full medical and neurologic workup. The differential diagnosis needs to include medical and neurologic diagnoses, including:

• delirium secondary to urinary tract infection
• Alzheimer’s and/or vascular dementia
• normal-pressure hydrocephalus
• substance abuse.

A complete dementia and delirium workup and detailed medical history are imperative.

FURTHER HISTORY: Risky behavior

Further history reveals that Mr. S had been having sexual intercourse with prostitutes since his early teens and that this habit continued into his 70s. He had been diagnosed with syphilis in his teens and again in his 50s. Both times he refused to complete the recommended penicillin regimen because he was embarrassed by the diagnosis and had falsely believed that a single penicillin injection would cure him.

Lab tests showed a white blood cell count of 3.5 and a weakly reactive serum venereal disease research laboratory (VDRL) reading.

Box 1

Could Mr. S’ syphilis—inadequately treated in his youth—be causing his depression and paranoia decades later? If so, how would you confirm this finding?

Dr. Greenberg’s and Tampi’s observations

Mr. S has a longstanding history of syphilis secondary to high-risk sexual activity. This, combined with the lab findings and his worsening depression and paranoia, points to possible neurosyphilis.

Syphilis, caused by the spirochete Treponema pallidum., can traverse mucous membranes and abraded skin. Transmission is most common during sexual activity but also occurs through blood transfusions and nonsexual lesion contact and from mother to fetus.

Box 2

Because syphilis and its psychiatric effects are relatively uncommon (Box 1), many psychiatrists do not consider neurosyphilis in high-risk patients who present with depression, dementia, or psychosis (Box 2).

HOW SYPHILIS BECOMES NEUROSYPHILIS

Primary syphilis incubates for 10 to 90 days following infection. After this period, an infectious chancre appears along with regional adenopathy. If untreated, the chancre will disappear but the infection will progress.

Secondary syphilis is characterized by skin manifestations and occasionally affects the joints, eyes, bones, kidneys, liver, and CNS. Common effects include condylomata—highly infectious warty lesions—and a diffuse maculopapular rash on the palms and soles. These lesions disappear if left untreated, but most patients then either enter syphilis’ latent stage or experience a potentially fatal relapse of secondary syphilis.⁵

Latent syphilis usually remains latent or resolves, but about one-third of patients with latent syphilis slowly progress to tertiary syphilis. Neurosyphilis, one of the main forms of tertiary syphilis, can surface 5 to 35 years after an untreated primary infection.⁷

There are four categories of neurosyphilis:

• General paresis results in dementia, changes in personality, transient hemiparesis, depression, and psychosis.
• Tabes dorsalis degenerates the posterior columns and dorsal root ganglia of the spinal cord. This results in ataxia, parasthesias, decreased proprioception and vibratory sense, Argyll Robertson pupil (an optical disorder in which the pupil does not react normally to light), neurogenic bladder, and sharp shooting pains throughout the body.
• Meningovascular neurosyphilis can result in cranial nerve abnormalities, symptoms of meningitis, and cerebral infarctions.
• Asymptomatic but with CSF positive for syphilis.

Neurosyphilis is fatal if untreated, and treatment usually does not eliminate symptoms but prevents further progression. Approximately 8% of patients with untreated primary syphilis develop neurosyphilis.^5,7

Standard nontreponemal tests, such as the VDRL or rapid plasmin reagin, can be used to screen for syphilis. Because these tests often produce false positives, confirm positive results with a syphilis-specific test, such as the fluorescent treponemal antibody absorption (FTA-ABS) test, microhemagglutination assay for antibodies to T pallidum., and the T pallidum. hemagglutination assay.

If neurosyphilis is suspected, CSF testing is strongly recommended. Diagnostic findings include elevated white blood cell and protein counts and a positive VDRL. If the CSF is negative, refer the patient for treatment anyway because false negatives are common. Patients with consistent neurologic symptoms, positive VDRL and/or FTA-ABS, and negative CSF are diagnosed with neurosyphilis and warrant treatment.⁷

How would you manage Mr. S’ psychiatric symptoms concomitant with medical treatment of late-stage syphilis?

Dr. Greenberg’s and Tampi’s observations

Although no specific guidelines exist for treating psychosis secondary to neurosyphilis, atypical antipsychotics remain the first-line treatment. Atypicals do not interact significantly with penicillin and can be given safely with syphilis treatment. Atypicals also are better tolerated than typical antipsychotics and produce fewer extrapyramidal symptoms, which are common among older patients and those with neurologic diseases.

Screening for syphilis. Every patient with a history of high-risk sexual behavior who presents with new-onset dementia or psychosis should be screened for syphilis. Sexual history can be difficult to obtain from some patients and family members, so communication between providers becomes crucial. Obtain lab test results from other care team members to monitor compliance, and coordinate patient education with other doctors on safe sexual practices.

TREATMENT: Taking his medicine

Mr. S refused further testing and emergency conservatorship was sought. Citalopram was discontinued and risperidone was gradually increased to 6 mg at bedtime. He remained paranoid and delusional.

A brain MRI showed chronic ischemic small-vessel disease. HIV testing was negative, and serum FTA-ABS was reactive. CSF showed elevated protein and white blood cell count with a nonreactive VDRL and a reactive FTA-ABS. A diagnosis of neurosyphilis was made, and treatment was initiated with aqueous crystalline penicillin G, 4 million units every 4 hours for 2 weeks.

Mr. S was discharged back to the nursing home where his penicillin injections were continued. His paranoia diminished slightly but he remained ataxic, incontinent, and confused. He was discharged from the nursing home but needed confirmative HIV screening and repeated CSF testing to determine if syphilis treatment was effective.

Six months after treatment, Mr. S’ niece reports that his paranoia has decreased. He has not needed additional psychiatric hospitalizations.

Related resources

• Merck Manual. www.merck.com. Search: “syphilis”
• U.S. Centers for Disease Control and Prevention—Syphilis elimination: History in the making. www.cdc.gov. Click on “Health Topics A-Z,” then click on “S” and find “syphilis.”
• National Institute of Allergy and Infectious Disease. www.niaid.nih.gov. Search: “syphilis”

Drug brand names