Supplement Editor:
Vincent W. Dennis, MD

Contents

Medical logic and coronary calcifications
V.W. Dennis, MD

Noninvasive quantification of coronary artery calcification: Methods and prognostic value
S.S. Halliburton, PhD; A.E. Stillman, MD, PhD; and R.D. White, MD

Coronary artery calcification and end-stage renal disease: Vascular biology and clinical implications
P. Schoenhagen, MD, and E.M. Tuzcu, MD

Cardiovascular mortality in chronic renal failure: Hyperphosphatemia, coronary calcification, and the role of phosphate binders
R.A. Fatica, MD, and V.W. Dennis, MD

Supplement Editor:
Vincent W. Dennis, MD

Contents

Medical logic and coronary calcifications
V.W. Dennis, MD

Noninvasive quantification of coronary artery calcification: Methods and prognostic value
S.S. Halliburton, PhD; A.E. Stillman, MD, PhD; and R.D. White, MD

Coronary artery calcification and end-stage renal disease: Vascular biology and clinical implications
P. Schoenhagen, MD, and E.M. Tuzcu, MD

Cardiovascular mortality in chronic renal failure: Hyperphosphatemia, coronary calcification, and the role of phosphate binders
R.A. Fatica, MD, and V.W. Dennis, MD

Supplement Editor:
Vincent W. Dennis, MD

Contents

Medical logic and coronary calcifications
V.W. Dennis, MD

Noninvasive quantification of coronary artery calcification: Methods and prognostic value
S.S. Halliburton, PhD; A.E. Stillman, MD, PhD; and R.D. White, MD

Coronary artery calcification and end-stage renal disease: Vascular biology and clinical implications
P. Schoenhagen, MD, and E.M. Tuzcu, MD

Cardiovascular mortality in chronic renal failure: Hyperphosphatemia, coronary calcification, and the role of phosphate binders
R.A. Fatica, MD, and V.W. Dennis, MD

Many of the 28 million people who suffer from migraine headaches each year¹ need psychiatric care in addition to headache relief. Migraine headaches often coexist with depression,² anxiety/panic disorders,^2,3 bipolar disorder,⁴ and phobias,⁵ as well as with stroke⁶ and epilepsy.⁷ A study of 995 young adults found that anxiety disorders, phobias, major depression, panic disorder, and obsessive-compulsive disorder were two to five times more prevalent among migraine sufferers than among a control group (Table 1 ).²

Migraine sufferers know that at any time an attack could hamper their ability to work, care for their families, or engage in social activities. A nationwide study of migraineurs found that attacks often impaired their relationships with family and friends.⁸

Psychiatrists should screen patients for a history of migraine or other headaches and carefully consider the relationship between migraines and psychiatric disorders when prescribing treatment. In this article, we outline acute and preventive headache treatments and present two cases to help you treat these patients appropriately.

Table 1

PSYCHIATRIC COMORBIDITIES IN PATIENTS WITH VS. WITHOUT MIGRAINES*

Table 2

THREE TYPES OF PRIMARY HEADACHE: DIAGNOSTIC CRITERIA

Headache definitions and diagnosis

Primary or secondary. Under the International Headache Society’s (IHS) 1988 headache classification and diagnostic criteria,⁹ headaches are primary or secondary:

• Primary headaches are benign recurrent headaches that commonly present in practice.
• Secondary headaches occur much less frequently and are caused by underlying pathology.

The possibility of secondary headache should be ruled out before a primary headache can be diagnosed. The following headache features should cause concern:

• Severe headache with abrupt onset
• Subacute or progressive headache over days or months
• Headache, nausea, vomiting, and fever not explained by systemic illness
• New-onset headache late in life
• Headache with neurologic signs or symptoms such as confusion, decreased level of consciousness, meningismus, or papilledema
• Headache following head trauma
• Patient history of sickle cell disease, malignancy, or HIV.

Headache types. The three major types of primary headache are migraine, tension-type, and cluster (Table 2 ). Tension-type is the most common, is often mild, and is either self-treated with over-the-counter medications or ignored. Migraine is the most troublesome headache in everyday practice. Cluster is the most severe and fortunately is rare.

Migraine with aura and migraine without aura are separate diagnoses. IHS criteria for diagnosing migraines without aura are listed in Table 3. According to the IHS, migraine with aura (or “classic migraine”) fulfills all the criteria for migraine without aura, with fully reversible neurologic symptoms indicating focal cerebral cortical and/or brain stem dysfunction.

Auras. About 15% of migraineurs experience auras. Symptoms develop within 5 to 20 minutes, usually last less than 1 hour, and fade before the headache’s onset. Gradual onset and history of previous attacks helps to distinguish aura from transient ischemic attacks. Auras may manifest as visual, sensory, motor, or brain-stem symptoms, or as combinations of these:

• Visual auras are most common, presenting as localized visual loss (scotoma), with flashing lights (scintillation) at margins or jagged edges (fortification).
• Sensory auras present as facial or limb paresthesias.
• Motor auras manifest as weakness or lack of coordination.
• Brain stem auras manifest as vertigo or double vision.

Migraine aura is considered part of the headache’s prodrome, which may occur days or hours before the headache’s onset. The aura may bring about:

• an altered mental state (e.g., depression, hyperactivity, euphoria, difficulty concentrating, dysphasia)
• neurologic symptoms (e.g., photophobia, phonophobia, hyperosmia, yawning)
• general bodily discomforts (e.g., anorexia, food craving, diarrhea, thirst, urination, fluid retention, cold feeling).

Despite their sometimes severe effects, migraines often remain undiagnosed.¹⁰ Migraine should be suspected in patients with recurrent moderate to severe disabling headaches (Box).^11-15

Case 1: “Bad, sick headaches”

Ms. A, 23, a single parent with a 2-year-old child, has had trouble staying employed because of repeated illnesses. She made 17 visits to her primary care physician within 26 months. While her main complaint was headache, she also complained of other aches and pains, a lack of energy, and insomnia. Numerous examinations revealed no physical abnormalities.

She reported having “bad, sick headaches” that sometimes lasted 2 to 3 days. Bed rest helped but this was not always possible. The headache was throbbing and usually one-sided. She had no aura, and ibuprofen gave partial relief. She noted that her mother gets similar headaches.

Table 3

DIAGNOSTIC REQUIREMENTS FOR MIGRAINE WITHOUT AURA

Ms. A was diagnosed with migraine without aura, and she was treated with sumatriptan, 100 mg (1 or 2 doses, as needed). Her headaches responded well to this treatment, but the frequency of attacks remained unchanged. She requested a change in her medicine.

Box

Treating migraines

Acute treatment. Migraineurs whose attacks are infrequent and mild may find OTC analgesics or NSAIDs adequate. Most patients, however, require specific migraine treatment, usually with triptans. Acute oral treatment options include sumatriptan, 50 to 100 mg; rizatriptan, 10 mg; zolmitriptan, 2.5 to 5 mg; and eletriptan, 40 mg.

In case of vomiting or nausea, options include sumatriptan, 20 mg nasal spray or 6 mg SC; rizatriptan, 10 mg on a dissolving wafer; or dihydroergotamine, 2 mg nasal spray or 1 mg IM or SC. For severe nausea or vomiting, an anti-nauseant (e.g., prochlorperazine suppositories, 25 mg) may be of value.

Preventive treatment. Preventive treatment may be warranted, depending on attack frequency, severity, and the extent of disability caused. One prolonged, severe attack per month that responds poorly to acute treatment may indicate the need for preventive treatment. A range of preventative treatments is available (Table 4).

In Ms. A’s case, oral sumatriptan lessened the severity of the migraine attacks, and the addition of nortriptyline, 50 mg/d, reduced frequency by about 50%. She felt more energetic overall and was sleeping better.

Treating the psychiatric comorbidity

Behavioral therapy is used as an adjunct to pharmacologic headache treatment. This approach is usually considered after a poor or adverse response to treatment, or when pharmacologic treatment is contraindicated (e.g., during pregnancy).

Relaxation training, biofeedback, and cognitive-behavioral stress management are the most commonly used forms of behavioral therapy. Thirty-five to 55% improvement in migraine has been reported following such treatments.¹⁶

Cognitive-behavioral intervention has been shown to be effective in depression¹⁷ and anxiety disorders.¹⁸ When either psychiatric problem is comorbid with migraine, cognitive therapy can improve both the migraine and the psychiatric comorbidity.

Pharmacologic therapy. Depression is commonly associated with migraine and may be caused by living with chronic disabling headaches over time. In such cases, the depression will improve as the migraine responds to treatment. However, in cases where comorbid depression or anxiety trigger or exacerbate acute migraine attacks, neither the migraine nor the psychiatric problem responds until the underlying psychopathology is treated. In such cases, simultaneous psychiatric and migraine pharmacologic treatment is required.

We recommend that you treat the psychiatric comorbidity as it would be treated without a co-existing migraine. Be advised, however, that monoamine oxidase inhibitors are contraindicated in depression during the 2 weeks before treating the comorbid migraine with a triptan. If the patient does not respond or if there is concern regarding possible underlying pathology, consult with a clinician who specializes in headache treatment.

Precipitating and aggravating factors

Headache triggers. Helping patients to recognize headache triggers and aggravating factors is an important element in treating and preventing migraines. Identifying these factors in the patient history can help you establish a diagnosis and implement steps to avoid or reduce attack severity.

Table 4

TREATMENT OPTIONS FOR PREVENTING MIGRAINE ATTACKS

Common migraine headache triggers include menstruation, stress, relaxation after stress, fatigue, too much or too little sleep, skipping meals, weather changes, high humidity, glare and flickering lights, loud or high-pitched noises, smoke or dust, strong perfumes or cooking aromas. Food triggers cause 10% of migraine cases. Chocolate, strong cheeses, red wine, beer, citrus fruits, and foods with monosodium glutamate and nitrate preservatives are common food triggers.

Tension-type headaches are triggered by stress or the end of a stress-filled day. Triggers for cluster-type headaches include alcohol, smoking during the cluster phase, and lying down during an attack.

Case 2: Flying the unfriendly skies

Ms. B, 38, is a mother of three who works as a flight attendant. She is separated from her husband and had filed for divorce because of repeated spousal abuse. She has visited her primary care physician multiple times for migraine, sinus problems, backache, and coccygodynia. Orthopedic and rectal examinations revealed no abnormalities.

Her headaches met the IHS diagnostic criteria for migraine with aura, and these responded well to zolmitriptan, 5 mg. The headaches usually occurred during days off from work, but her sinus problems also led to headaches and nasal stuffiness when she flew. Her headaches eventually occurred almost daily.

Her supervisor was unsympathetic. An otolaryngologist had prescribed decongestants and a course of desensitization, both of which brought only transient relief.

A counselor at work recommended that Ms. B go on sick leave and accept a transfer to a non-flying job. The patient was tearful and felt overwhelmed by her problems. She felt that life was no longer worth living. She agreed to see a psychiatrist, who diagnosed depression and anxiety disorder. The psychiatrist prescribed citalopram, 20 mg/d, and agreed to see her regularly to monitor progress.

Discussion. As a migraineur, Ms. B was at increased risk for depression and anxiety disorders.¹⁹ Migraine with aura is associated with an increased lifetime prevalence of suicidal ideation and suicide attempts.²⁰

The exact mechanisms by which migraine and depression are related are unknown. Each disorder increases the risk for developing the other. The specificity of this relationship is strengthened by the fact that depression is not associated with a greater risk of severe nonmigrainous headache, even though a severe nonmigrainous headache may cause depression.²¹

The patient in case 1 responded well when an antidepressant was added to her treatment. In her case, the diagnosis of a depressive disorder remained an open question. Migraine attacks are known to be associated with mood change, lethargy, and cognitive changes. The picture may be further confounded because migraine without depression responds well to prophylaxis with antidepressants.

The patient in case 2, however, presented with a complex of interrelated headache and psychiatric problems of potentially dangerous proportions. Psychiatric problems in migraineurs may be deep-seated, and these patients may require urgent, specialized attention to avoid further serious disability and a possible tragic outcome.

Related resources

• Silberstein SD, Lipton RB, Goadsby PJ, Smith, R, eds. Headache in primary care. Oxford, UK: Isis Medical Media, 1999.
• Silberstein SD, Lipton RB, Dalessio DJ. Wolff’s headache and other head pain (7th ed). New York: Oxford University Press, 2001.
• Davidoff RA. Migraine. Manifestations, pathogenesis and management (2nd ed). New York: Oxford University Press, 2002.
• International Headache Society. http://www.i-h-s.org

Drug brand names

• Citalopram • Celexa
• Dihydroergotamine • Migranal
• Eletriptan • Relpax
• Rizatriptan • Maxalt
• Sumatriptan • Imitrex
• Valproate sodium • Depakote
• Zolmitriptan • Zomig

Disclosure

Dr. Smith reports that he serves as a consultant to and is on the speakers’ bureau of AstraZeneca Pharmaceuticals.

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

Many of the 28 million people who suffer from migraine headaches each year¹ need psychiatric care in addition to headache relief. Migraine headaches often coexist with depression,² anxiety/panic disorders,^2,3 bipolar disorder,⁴ and phobias,⁵ as well as with stroke⁶ and epilepsy.⁷ A study of 995 young adults found that anxiety disorders, phobias, major depression, panic disorder, and obsessive-compulsive disorder were two to five times more prevalent among migraine sufferers than among a control group (Table 1 ).²

Migraine sufferers know that at any time an attack could hamper their ability to work, care for their families, or engage in social activities. A nationwide study of migraineurs found that attacks often impaired their relationships with family and friends.⁸

Psychiatrists should screen patients for a history of migraine or other headaches and carefully consider the relationship between migraines and psychiatric disorders when prescribing treatment. In this article, we outline acute and preventive headache treatments and present two cases to help you treat these patients appropriately.

Table 1

PSYCHIATRIC COMORBIDITIES IN PATIENTS WITH VS. WITHOUT MIGRAINES*

Table 2

THREE TYPES OF PRIMARY HEADACHE: DIAGNOSTIC CRITERIA

Headache definitions and diagnosis

Primary or secondary. Under the International Headache Society’s (IHS) 1988 headache classification and diagnostic criteria,⁹ headaches are primary or secondary:

• Primary headaches are benign recurrent headaches that commonly present in practice.
• Secondary headaches occur much less frequently and are caused by underlying pathology.

The possibility of secondary headache should be ruled out before a primary headache can be diagnosed. The following headache features should cause concern:

• Severe headache with abrupt onset
• Subacute or progressive headache over days or months
• Headache, nausea, vomiting, and fever not explained by systemic illness
• New-onset headache late in life
• Headache with neurologic signs or symptoms such as confusion, decreased level of consciousness, meningismus, or papilledema
• Headache following head trauma
• Patient history of sickle cell disease, malignancy, or HIV.

Headache types. The three major types of primary headache are migraine, tension-type, and cluster (Table 2 ). Tension-type is the most common, is often mild, and is either self-treated with over-the-counter medications or ignored. Migraine is the most troublesome headache in everyday practice. Cluster is the most severe and fortunately is rare.

Migraine with aura and migraine without aura are separate diagnoses. IHS criteria for diagnosing migraines without aura are listed in Table 3. According to the IHS, migraine with aura (or “classic migraine”) fulfills all the criteria for migraine without aura, with fully reversible neurologic symptoms indicating focal cerebral cortical and/or brain stem dysfunction.

Auras. About 15% of migraineurs experience auras. Symptoms develop within 5 to 20 minutes, usually last less than 1 hour, and fade before the headache’s onset. Gradual onset and history of previous attacks helps to distinguish aura from transient ischemic attacks. Auras may manifest as visual, sensory, motor, or brain-stem symptoms, or as combinations of these:

• Visual auras are most common, presenting as localized visual loss (scotoma), with flashing lights (scintillation) at margins or jagged edges (fortification).
• Sensory auras present as facial or limb paresthesias.
• Motor auras manifest as weakness or lack of coordination.
• Brain stem auras manifest as vertigo or double vision.

Migraine aura is considered part of the headache’s prodrome, which may occur days or hours before the headache’s onset. The aura may bring about:

• an altered mental state (e.g., depression, hyperactivity, euphoria, difficulty concentrating, dysphasia)
• neurologic symptoms (e.g., photophobia, phonophobia, hyperosmia, yawning)
• general bodily discomforts (e.g., anorexia, food craving, diarrhea, thirst, urination, fluid retention, cold feeling).

Despite their sometimes severe effects, migraines often remain undiagnosed.¹⁰ Migraine should be suspected in patients with recurrent moderate to severe disabling headaches (Box).^11-15

Case 1: “Bad, sick headaches”

Ms. A, 23, a single parent with a 2-year-old child, has had trouble staying employed because of repeated illnesses. She made 17 visits to her primary care physician within 26 months. While her main complaint was headache, she also complained of other aches and pains, a lack of energy, and insomnia. Numerous examinations revealed no physical abnormalities.

She reported having “bad, sick headaches” that sometimes lasted 2 to 3 days. Bed rest helped but this was not always possible. The headache was throbbing and usually one-sided. She had no aura, and ibuprofen gave partial relief. She noted that her mother gets similar headaches.

Table 3

DIAGNOSTIC REQUIREMENTS FOR MIGRAINE WITHOUT AURA

Ms. A was diagnosed with migraine without aura, and she was treated with sumatriptan, 100 mg (1 or 2 doses, as needed). Her headaches responded well to this treatment, but the frequency of attacks remained unchanged. She requested a change in her medicine.

Box

Treating migraines

Acute treatment. Migraineurs whose attacks are infrequent and mild may find OTC analgesics or NSAIDs adequate. Most patients, however, require specific migraine treatment, usually with triptans. Acute oral treatment options include sumatriptan, 50 to 100 mg; rizatriptan, 10 mg; zolmitriptan, 2.5 to 5 mg; and eletriptan, 40 mg.

In case of vomiting or nausea, options include sumatriptan, 20 mg nasal spray or 6 mg SC; rizatriptan, 10 mg on a dissolving wafer; or dihydroergotamine, 2 mg nasal spray or 1 mg IM or SC. For severe nausea or vomiting, an anti-nauseant (e.g., prochlorperazine suppositories, 25 mg) may be of value.

Preventive treatment. Preventive treatment may be warranted, depending on attack frequency, severity, and the extent of disability caused. One prolonged, severe attack per month that responds poorly to acute treatment may indicate the need for preventive treatment. A range of preventative treatments is available (Table 4).

In Ms. A’s case, oral sumatriptan lessened the severity of the migraine attacks, and the addition of nortriptyline, 50 mg/d, reduced frequency by about 50%. She felt more energetic overall and was sleeping better.

Treating the psychiatric comorbidity

Behavioral therapy is used as an adjunct to pharmacologic headache treatment. This approach is usually considered after a poor or adverse response to treatment, or when pharmacologic treatment is contraindicated (e.g., during pregnancy).

Relaxation training, biofeedback, and cognitive-behavioral stress management are the most commonly used forms of behavioral therapy. Thirty-five to 55% improvement in migraine has been reported following such treatments.¹⁶

Cognitive-behavioral intervention has been shown to be effective in depression¹⁷ and anxiety disorders.¹⁸ When either psychiatric problem is comorbid with migraine, cognitive therapy can improve both the migraine and the psychiatric comorbidity.

Pharmacologic therapy. Depression is commonly associated with migraine and may be caused by living with chronic disabling headaches over time. In such cases, the depression will improve as the migraine responds to treatment. However, in cases where comorbid depression or anxiety trigger or exacerbate acute migraine attacks, neither the migraine nor the psychiatric problem responds until the underlying psychopathology is treated. In such cases, simultaneous psychiatric and migraine pharmacologic treatment is required.

We recommend that you treat the psychiatric comorbidity as it would be treated without a co-existing migraine. Be advised, however, that monoamine oxidase inhibitors are contraindicated in depression during the 2 weeks before treating the comorbid migraine with a triptan. If the patient does not respond or if there is concern regarding possible underlying pathology, consult with a clinician who specializes in headache treatment.

Precipitating and aggravating factors

Headache triggers. Helping patients to recognize headache triggers and aggravating factors is an important element in treating and preventing migraines. Identifying these factors in the patient history can help you establish a diagnosis and implement steps to avoid or reduce attack severity.

Table 4

TREATMENT OPTIONS FOR PREVENTING MIGRAINE ATTACKS

Common migraine headache triggers include menstruation, stress, relaxation after stress, fatigue, too much or too little sleep, skipping meals, weather changes, high humidity, glare and flickering lights, loud or high-pitched noises, smoke or dust, strong perfumes or cooking aromas. Food triggers cause 10% of migraine cases. Chocolate, strong cheeses, red wine, beer, citrus fruits, and foods with monosodium glutamate and nitrate preservatives are common food triggers.

Tension-type headaches are triggered by stress or the end of a stress-filled day. Triggers for cluster-type headaches include alcohol, smoking during the cluster phase, and lying down during an attack.

Case 2: Flying the unfriendly skies

Ms. B, 38, is a mother of three who works as a flight attendant. She is separated from her husband and had filed for divorce because of repeated spousal abuse. She has visited her primary care physician multiple times for migraine, sinus problems, backache, and coccygodynia. Orthopedic and rectal examinations revealed no abnormalities.

Her headaches met the IHS diagnostic criteria for migraine with aura, and these responded well to zolmitriptan, 5 mg. The headaches usually occurred during days off from work, but her sinus problems also led to headaches and nasal stuffiness when she flew. Her headaches eventually occurred almost daily.

Her supervisor was unsympathetic. An otolaryngologist had prescribed decongestants and a course of desensitization, both of which brought only transient relief.

A counselor at work recommended that Ms. B go on sick leave and accept a transfer to a non-flying job. The patient was tearful and felt overwhelmed by her problems. She felt that life was no longer worth living. She agreed to see a psychiatrist, who diagnosed depression and anxiety disorder. The psychiatrist prescribed citalopram, 20 mg/d, and agreed to see her regularly to monitor progress.

Discussion. As a migraineur, Ms. B was at increased risk for depression and anxiety disorders.¹⁹ Migraine with aura is associated with an increased lifetime prevalence of suicidal ideation and suicide attempts.²⁰

The exact mechanisms by which migraine and depression are related are unknown. Each disorder increases the risk for developing the other. The specificity of this relationship is strengthened by the fact that depression is not associated with a greater risk of severe nonmigrainous headache, even though a severe nonmigrainous headache may cause depression.²¹

The patient in case 1 responded well when an antidepressant was added to her treatment. In her case, the diagnosis of a depressive disorder remained an open question. Migraine attacks are known to be associated with mood change, lethargy, and cognitive changes. The picture may be further confounded because migraine without depression responds well to prophylaxis with antidepressants.

The patient in case 2, however, presented with a complex of interrelated headache and psychiatric problems of potentially dangerous proportions. Psychiatric problems in migraineurs may be deep-seated, and these patients may require urgent, specialized attention to avoid further serious disability and a possible tragic outcome.

Related resources

• Silberstein SD, Lipton RB, Goadsby PJ, Smith, R, eds. Headache in primary care. Oxford, UK: Isis Medical Media, 1999.
• Silberstein SD, Lipton RB, Dalessio DJ. Wolff’s headache and other head pain (7th ed). New York: Oxford University Press, 2001.
• Davidoff RA. Migraine. Manifestations, pathogenesis and management (2nd ed). New York: Oxford University Press, 2002.
• International Headache Society. http://www.i-h-s.org

Drug brand names

• Citalopram • Celexa
• Dihydroergotamine • Migranal
• Eletriptan • Relpax
• Rizatriptan • Maxalt
• Sumatriptan • Imitrex
• Valproate sodium • Depakote
• Zolmitriptan • Zomig

Disclosure

Dr. Smith reports that he serves as a consultant to and is on the speakers’ bureau of AstraZeneca Pharmaceuticals.

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

Many of the 28 million people who suffer from migraine headaches each year¹ need psychiatric care in addition to headache relief. Migraine headaches often coexist with depression,² anxiety/panic disorders,^2,3 bipolar disorder,⁴ and phobias,⁵ as well as with stroke⁶ and epilepsy.⁷ A study of 995 young adults found that anxiety disorders, phobias, major depression, panic disorder, and obsessive-compulsive disorder were two to five times more prevalent among migraine sufferers than among a control group (Table 1 ).²

Migraine sufferers know that at any time an attack could hamper their ability to work, care for their families, or engage in social activities. A nationwide study of migraineurs found that attacks often impaired their relationships with family and friends.⁸

Psychiatrists should screen patients for a history of migraine or other headaches and carefully consider the relationship between migraines and psychiatric disorders when prescribing treatment. In this article, we outline acute and preventive headache treatments and present two cases to help you treat these patients appropriately.

Table 1

PSYCHIATRIC COMORBIDITIES IN PATIENTS WITH VS. WITHOUT MIGRAINES*

Table 2

THREE TYPES OF PRIMARY HEADACHE: DIAGNOSTIC CRITERIA

Headache definitions and diagnosis

Primary or secondary. Under the International Headache Society’s (IHS) 1988 headache classification and diagnostic criteria,⁹ headaches are primary or secondary:

• Primary headaches are benign recurrent headaches that commonly present in practice.
• Secondary headaches occur much less frequently and are caused by underlying pathology.

The possibility of secondary headache should be ruled out before a primary headache can be diagnosed. The following headache features should cause concern:

• Severe headache with abrupt onset
• Subacute or progressive headache over days or months
• Headache, nausea, vomiting, and fever not explained by systemic illness
• New-onset headache late in life
• Headache with neurologic signs or symptoms such as confusion, decreased level of consciousness, meningismus, or papilledema
• Headache following head trauma
• Patient history of sickle cell disease, malignancy, or HIV.

Headache types. The three major types of primary headache are migraine, tension-type, and cluster (Table 2 ). Tension-type is the most common, is often mild, and is either self-treated with over-the-counter medications or ignored. Migraine is the most troublesome headache in everyday practice. Cluster is the most severe and fortunately is rare.

Migraine with aura and migraine without aura are separate diagnoses. IHS criteria for diagnosing migraines without aura are listed in Table 3. According to the IHS, migraine with aura (or “classic migraine”) fulfills all the criteria for migraine without aura, with fully reversible neurologic symptoms indicating focal cerebral cortical and/or brain stem dysfunction.

Auras. About 15% of migraineurs experience auras. Symptoms develop within 5 to 20 minutes, usually last less than 1 hour, and fade before the headache’s onset. Gradual onset and history of previous attacks helps to distinguish aura from transient ischemic attacks. Auras may manifest as visual, sensory, motor, or brain-stem symptoms, or as combinations of these:

• Visual auras are most common, presenting as localized visual loss (scotoma), with flashing lights (scintillation) at margins or jagged edges (fortification).
• Sensory auras present as facial or limb paresthesias.
• Motor auras manifest as weakness or lack of coordination.
• Brain stem auras manifest as vertigo or double vision.

Migraine aura is considered part of the headache’s prodrome, which may occur days or hours before the headache’s onset. The aura may bring about:

• an altered mental state (e.g., depression, hyperactivity, euphoria, difficulty concentrating, dysphasia)
• neurologic symptoms (e.g., photophobia, phonophobia, hyperosmia, yawning)
• general bodily discomforts (e.g., anorexia, food craving, diarrhea, thirst, urination, fluid retention, cold feeling).

Despite their sometimes severe effects, migraines often remain undiagnosed.¹⁰ Migraine should be suspected in patients with recurrent moderate to severe disabling headaches (Box).^11-15

Case 1: “Bad, sick headaches”

Ms. A, 23, a single parent with a 2-year-old child, has had trouble staying employed because of repeated illnesses. She made 17 visits to her primary care physician within 26 months. While her main complaint was headache, she also complained of other aches and pains, a lack of energy, and insomnia. Numerous examinations revealed no physical abnormalities.

She reported having “bad, sick headaches” that sometimes lasted 2 to 3 days. Bed rest helped but this was not always possible. The headache was throbbing and usually one-sided. She had no aura, and ibuprofen gave partial relief. She noted that her mother gets similar headaches.

Table 3

DIAGNOSTIC REQUIREMENTS FOR MIGRAINE WITHOUT AURA

Ms. A was diagnosed with migraine without aura, and she was treated with sumatriptan, 100 mg (1 or 2 doses, as needed). Her headaches responded well to this treatment, but the frequency of attacks remained unchanged. She requested a change in her medicine.

Box

Treating migraines

Acute treatment. Migraineurs whose attacks are infrequent and mild may find OTC analgesics or NSAIDs adequate. Most patients, however, require specific migraine treatment, usually with triptans. Acute oral treatment options include sumatriptan, 50 to 100 mg; rizatriptan, 10 mg; zolmitriptan, 2.5 to 5 mg; and eletriptan, 40 mg.

In case of vomiting or nausea, options include sumatriptan, 20 mg nasal spray or 6 mg SC; rizatriptan, 10 mg on a dissolving wafer; or dihydroergotamine, 2 mg nasal spray or 1 mg IM or SC. For severe nausea or vomiting, an anti-nauseant (e.g., prochlorperazine suppositories, 25 mg) may be of value.

Preventive treatment. Preventive treatment may be warranted, depending on attack frequency, severity, and the extent of disability caused. One prolonged, severe attack per month that responds poorly to acute treatment may indicate the need for preventive treatment. A range of preventative treatments is available (Table 4).

In Ms. A’s case, oral sumatriptan lessened the severity of the migraine attacks, and the addition of nortriptyline, 50 mg/d, reduced frequency by about 50%. She felt more energetic overall and was sleeping better.

Treating the psychiatric comorbidity

Behavioral therapy is used as an adjunct to pharmacologic headache treatment. This approach is usually considered after a poor or adverse response to treatment, or when pharmacologic treatment is contraindicated (e.g., during pregnancy).

Relaxation training, biofeedback, and cognitive-behavioral stress management are the most commonly used forms of behavioral therapy. Thirty-five to 55% improvement in migraine has been reported following such treatments.¹⁶

Cognitive-behavioral intervention has been shown to be effective in depression¹⁷ and anxiety disorders.¹⁸ When either psychiatric problem is comorbid with migraine, cognitive therapy can improve both the migraine and the psychiatric comorbidity.

Pharmacologic therapy. Depression is commonly associated with migraine and may be caused by living with chronic disabling headaches over time. In such cases, the depression will improve as the migraine responds to treatment. However, in cases where comorbid depression or anxiety trigger or exacerbate acute migraine attacks, neither the migraine nor the psychiatric problem responds until the underlying psychopathology is treated. In such cases, simultaneous psychiatric and migraine pharmacologic treatment is required.

We recommend that you treat the psychiatric comorbidity as it would be treated without a co-existing migraine. Be advised, however, that monoamine oxidase inhibitors are contraindicated in depression during the 2 weeks before treating the comorbid migraine with a triptan. If the patient does not respond or if there is concern regarding possible underlying pathology, consult with a clinician who specializes in headache treatment.

Precipitating and aggravating factors

Headache triggers. Helping patients to recognize headache triggers and aggravating factors is an important element in treating and preventing migraines. Identifying these factors in the patient history can help you establish a diagnosis and implement steps to avoid or reduce attack severity.

Table 4

TREATMENT OPTIONS FOR PREVENTING MIGRAINE ATTACKS

Common migraine headache triggers include menstruation, stress, relaxation after stress, fatigue, too much or too little sleep, skipping meals, weather changes, high humidity, glare and flickering lights, loud or high-pitched noises, smoke or dust, strong perfumes or cooking aromas. Food triggers cause 10% of migraine cases. Chocolate, strong cheeses, red wine, beer, citrus fruits, and foods with monosodium glutamate and nitrate preservatives are common food triggers.

Tension-type headaches are triggered by stress or the end of a stress-filled day. Triggers for cluster-type headaches include alcohol, smoking during the cluster phase, and lying down during an attack.

Case 2: Flying the unfriendly skies

Ms. B, 38, is a mother of three who works as a flight attendant. She is separated from her husband and had filed for divorce because of repeated spousal abuse. She has visited her primary care physician multiple times for migraine, sinus problems, backache, and coccygodynia. Orthopedic and rectal examinations revealed no abnormalities.

Her headaches met the IHS diagnostic criteria for migraine with aura, and these responded well to zolmitriptan, 5 mg. The headaches usually occurred during days off from work, but her sinus problems also led to headaches and nasal stuffiness when she flew. Her headaches eventually occurred almost daily.

Her supervisor was unsympathetic. An otolaryngologist had prescribed decongestants and a course of desensitization, both of which brought only transient relief.

A counselor at work recommended that Ms. B go on sick leave and accept a transfer to a non-flying job. The patient was tearful and felt overwhelmed by her problems. She felt that life was no longer worth living. She agreed to see a psychiatrist, who diagnosed depression and anxiety disorder. The psychiatrist prescribed citalopram, 20 mg/d, and agreed to see her regularly to monitor progress.

Discussion. As a migraineur, Ms. B was at increased risk for depression and anxiety disorders.¹⁹ Migraine with aura is associated with an increased lifetime prevalence of suicidal ideation and suicide attempts.²⁰

The exact mechanisms by which migraine and depression are related are unknown. Each disorder increases the risk for developing the other. The specificity of this relationship is strengthened by the fact that depression is not associated with a greater risk of severe nonmigrainous headache, even though a severe nonmigrainous headache may cause depression.²¹

The patient in case 1 responded well when an antidepressant was added to her treatment. In her case, the diagnosis of a depressive disorder remained an open question. Migraine attacks are known to be associated with mood change, lethargy, and cognitive changes. The picture may be further confounded because migraine without depression responds well to prophylaxis with antidepressants.

The patient in case 2, however, presented with a complex of interrelated headache and psychiatric problems of potentially dangerous proportions. Psychiatric problems in migraineurs may be deep-seated, and these patients may require urgent, specialized attention to avoid further serious disability and a possible tragic outcome.

Related resources

• Silberstein SD, Lipton RB, Goadsby PJ, Smith, R, eds. Headache in primary care. Oxford, UK: Isis Medical Media, 1999.
• Silberstein SD, Lipton RB, Dalessio DJ. Wolff’s headache and other head pain (7th ed). New York: Oxford University Press, 2001.
• Davidoff RA. Migraine. Manifestations, pathogenesis and management (2nd ed). New York: Oxford University Press, 2002.
• International Headache Society. http://www.i-h-s.org

Drug brand names

• Citalopram • Celexa
• Dihydroergotamine • Migranal
• Eletriptan • Relpax
• Rizatriptan • Maxalt
• Sumatriptan • Imitrex
• Valproate sodium • Depakote
• Zolmitriptan • Zomig

Disclosure

Dr. Smith reports that he serves as a consultant to and is on the speakers’ bureau of AstraZeneca Pharmaceuticals.

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

History: Living in fear

Mr. I, 41, presents for an initial psychiatric evaluation. He saw a psychologist 8 years ago for a “mild depression,” which he described as a lack of motivation and difficulty concentrating. His mood has been chronically “flat” for the last 10 years. He complains of poor energy and decreased sleep because of irregular work hours, and admits to using over-the-counter caffeine pills to help him function.

The patient denies suicidal ideations, symptoms of guilt, psychotic symptoms, or crying spells, but has a history of alcoholism and cocaine abuse. (He has been sober for 5 years.) Significant recent stressors include a recent breakup with his girlfriend, which he adds “really hasn’t bothered me at all.”

Mr. I has been increasingly avoiding social situations. Though he denies having panic attacks, interaction with other people triggers shortness of breath and chest tight-ness, especially when speaking in public to strangers.

The fear of what others might think of him is dominating Mr. I’s life. For example, he would like to console a housemate whose mother died, but because he is afraid of how the friend will react, Mr. I has not approached him. He adds that he goes out of his way to avoid contact with his co-workers, working irregular hours and eating his lunch in his car rather than the office lounge—even in inclement weather.

Mr. I does attend Alcoholic Anonymous meetings, but often sits toward the back. He had led some meetings, but refused to even look up from the podium while doing so. His anxiety worsened, his heart rate increased, and his palms sweated while leading the group. He began attending different AA meetings so that others would not recognize him and volunteer him to lead.

He adds that he feels comfortable meeting and dating women, since these exchanges are “scripted.” As he gets to know his partner better, however, Mr. I becomes more self-conscious.

Which of Mr. I’s symptoms would you address first: the depressive or the phobic?

Drs. Yu’s, Gordon’s, and Maguire’s observations

Based on Mr. I’s presentation, one might at first diagnose major depressive disorder, but chronic avoidance patterns differentiate his illness from an endogenous depression. Mr. I was diagnosed as having social phobia, a disorder that has been gaining attention among researchers.

A phobia is defined as an irrational fear that produces conscious avoidance of the feared subject, activity, or situation. The presence or anticipation of the phobic entity elicits severe distress, though the affected person usually recognizes that the reaction is excessive. DSM-IV defines social phobia as a strong, persisting fear of potentially embarrassing situations (Box).¹

Two peaks of onset have been described: one occurring before age 5, and the other between ages 11 and 17.² The mean age of onset has been reported to be 15.²

Box

DSM-IV describes two types of social phobia: generalized social phobia and performance phobia. Normal fear and shyness should be differentiated from social phobia. Medical conditions—including CNS tumors and cerebrovascular diseases—and drugs typically bring about neurologic and mental status symptoms that can confound the diagnosis.

Symptoms of other anxiety disorders, including panic disorder and agoraphobia, may mimic social phobia. Fear in social phobia is not present outside of, or in anticipation of, the feared situation. Social phobia also can be misdiagnosed as an avoidant personality, schizoid personality, or major depressive disorder.¹

At this point, one should consider diagnosing Mr. I with social phobia, as evinced by his excessive avoidance of social situations. Mr. I also recognizes that his avoidance is excessive and causes difficulty in his daily functioning.

Behavioral inhibition in childhood is suggested to be more common in children with parents who had panic disorder. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.^5-7’

First treatment: Pharmacotherapy and psychotherapy

Mr. I is interested in trying an antidepressant, but noted that about 6 years ago a brief course of a selective serotonin reuptake inhibitor led to difficulty sleeping and decreased libido and orgasm. He agrees to take bupropion SR, 100 mg/d, titrated after 2 weeks to 100 mg bid.

He also begins cognitive-behavioral and supportive therapy, during which he reveals that his pattern of avoidance took root in grade school, where he was often a quiet sidekick to the popular kids. During therapy, he describes visitations with his daughters, both of whom live with his ex-wife, as extremely difficult.

“I really don’t know what to say,” Mr. I says. “We often stare at each other during dessert, and I want to get it over with and go home.”

After 1 month, his bupropion SR is increased to 150 mg bid. One month later, his feelings of depression are under control. He sleeps well, no longer feels fatigued, and can concentrate. Still he isolates himself, fearing others’ disapproval. He has become more resistant to psychotherapy. “I know my patterns. I know what I do, but I can’t change it,” he says.

How would you treat Mr. I’s persistent social phobia? Would you switch his medications or augment existing ones? Does psychotherapy still have a role in treatment?

Drs. Yu’s, Gordon’s, and Maguire’s observations

Pharmacologic treatment of social phobia has spawned several neurochemical hypotheses. As beta-adrenergic antagonists have been proven efficacious in treating performance phobia, an adrenergic hypothesis suggests patients with performance phobia release more norepinephrine and epinephrine or are more sensitive to normal levels of these neuro-transmitters.⁸

The success of monoamine oxidase inhibitors in generalized social phobia suggests that dopamine plays a role in treating this form of the disorder. Central dopamine activity has been associated with positive emotions or extraversion.⁹

SSRIs have also demonstrated efficacy against generalized social phobia.¹⁰ Researchers have associated higher serotonin levels with increased social dominance¹¹ and suggest that abnormal dopamine and serotonin levels contribute to the disorder’s pathogenesis.

Current treatments include psychotherapy and pharmacotherapy, and studies suggest that a combination of the two may be more efficacious than either alone.⁸ Venlafaxine, phenelzine, buspirone, benzodiazepines, and SSRIs have all demonstrated effectiveness and tolerability in generalized social phobia. Beta-adrenergic receptor antagonists (e.g., atenolol, propranolol) are commonly administered to treat performance phobia shortly before exposure to the phobic stimulus.

An adequate time frame for psychopharmacologic treatment of social phobia has not been defined. In depression therapy, medications should be maintained for at least 4 to 5 weeks before considering the regimen unsuccessful.¹

While Mr. I’s depression responded well to bupropion SR, a medication whose mechanism involves dopamine and norepinephrine reuptake, use of a medication that augments his serotonin may further improve his condition.

Cognitive and behavioral therapies also are indicated for both generalized social phobia and performance phobia. These should be considered along with medication therapy for Mr. I to treat his social phobia and prevent a relapse.

Despite the available evidence, however, the course and prognosis of social phobia are not clear. Data are still forthcoming on this recently recognized disorder.

Further treatment: Another neurotransmitter

Again cautious of potential adverse sexual effects, Mr. I agrees to try mirtazapine, 30 mg at bedtime, in addition to bupropion SR. He initially complains of sedation and lowered energy, but is willing to continue the mirtazapine, hoping that it will help his social phobia.

Two months after starting mirtazapine, Mr. I is still fearful at work and home, and his relationship with his order. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.^5-7’ daughters has not improved. After another month, he reports that his sedation has resolved, but complains of increased fatigue and difficulty concentrating. He suspects that the bupropion SR has stopped working.

After another month, Mr. I self-discontinues the mirtazapine. Though he tries to participate in social situations, his anxiety has worsened. He goes to a country music club once a week but is afraid to ask anyone to dance.

Should you focus on Mr. I’s depression rather than his social phobia? If so, how do you change his treatment?

Drs. Yu’s, Gordon’s, and Maguire’s observations

The severity of Mr. I’s social phobia may be causing his depression. Both trials of bupropion SR and mirtazapine have been adequate for his depression but have not alleviated his social phobia.

Medications that affect gamma-aminobutyric acid (GABA) levels, specifically benzodiazepines, have not been tried. Benzodiazepines provide rapid relief with little risk in short-term treatment, but dependence/withdrawal risks increase greatly when given more than 4 to 6 months.⁸ Because of Mr. I’s chronic anxiety in social phobia and his history of alcoholism, benzodiazepines are not recommended.

The novel compound tiagabine has been shown to increase GABA in the synaptic cleft.¹² GABA increases chloride conduction through its ligand-gated channels, creating a potential antianxiety effect similar to that produced by benzodiazepines.^8,13,14 GAT-1, the predominant transporter, removes excess GABA.

Just as SSRIs inhibit serotonin reuptake and allow the neurotransmitter to act on its receptors to alleviate depression and anxiety, so does tiagabine inhibit GAT-1. Theoretically, tiagabine may relieve anxiety by increasing synaptic concentrations of GABA.

Tiagabine also has been shown to be well-tolerated without a known abuse or dependence potential.¹² Possible adverse effects include impaired concentration, somnolence, fatigue, nausea, and dizziness. To avoid adverse effects, slow titration (about 4 mg per week) is recommended.

Changing treatment: Looking up

Tiagabine, 4 mg at bedtime, is added to help with Mr. I’s anxiety; he is instructed to increase the dosage by 4 mg every 5 days in divided doses. He began to sense improvement during the second week, at 4 mg bid, and 2 weeks later his anxiety has been greatly reduced. He can now sit quietly with his co-workers during coffee breaks and has begun training a co-worker, which he never dared to attempt before. At this point, he was tolerating tiagabine at 8 mg bid.

One month later, tiagabine is increased to 16 mg bid. Mr. I has noticed mild dizziness with each dosage increase, but each time it subsided within a day. He has been maintained on 16 mg bid.

Saying that his anxiety is now well-controlled, Mr. I enjoys at least one dance each week at the country music club he frequents. One week later, he led an Alcoholics Anonymous meeting—while looking up to his audience for the first time. He continues these activities and his therapy sessions, which are geared toward developing stronger skills to minimize his anxiety. He is considering lowering his medication dosages (though he is wary of a possible relapse) and furthering his therapy.

Related resources

• Anxiety Disorders Association of America www.adaa.org
• National Institute of Mental Health: Phobias from NLM’s MEDLINEplus http://www.nlm.nih.gov/medlineplus/phobias.html

Author affiliations

Dr. Yu is a fellow in child and adolescent psychiatry, Dr. Gordon is a resident physician; and Dr. Maguire is assistant dean for continuing medical education, director of resident training, and associate clinical professor, department of psychiatry, University of California, Irvine.

Drug brand names

• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Mirtazapine • Remeron
• Phenelzine • Nardil
• Tiagabine • Gabitril
• Venlafaxine • Effexor

Disclosure

Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc., Novartis Pharmaceuticals Corp., and Pfizer Inc., and receives research/grant support from and serves as a consultant to Eli Lilly and Co.

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

Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly and Co., is on the speaker’s bureau of Pfizer Inc., and receives research/grant support from Forest Laboratories and GlaxoSmithKline.

History: Living in fear

Mr. I, 41, presents for an initial psychiatric evaluation. He saw a psychologist 8 years ago for a “mild depression,” which he described as a lack of motivation and difficulty concentrating. His mood has been chronically “flat” for the last 10 years. He complains of poor energy and decreased sleep because of irregular work hours, and admits to using over-the-counter caffeine pills to help him function.

The patient denies suicidal ideations, symptoms of guilt, psychotic symptoms, or crying spells, but has a history of alcoholism and cocaine abuse. (He has been sober for 5 years.) Significant recent stressors include a recent breakup with his girlfriend, which he adds “really hasn’t bothered me at all.”

Mr. I has been increasingly avoiding social situations. Though he denies having panic attacks, interaction with other people triggers shortness of breath and chest tight-ness, especially when speaking in public to strangers.

The fear of what others might think of him is dominating Mr. I’s life. For example, he would like to console a housemate whose mother died, but because he is afraid of how the friend will react, Mr. I has not approached him. He adds that he goes out of his way to avoid contact with his co-workers, working irregular hours and eating his lunch in his car rather than the office lounge—even in inclement weather.

Mr. I does attend Alcoholic Anonymous meetings, but often sits toward the back. He had led some meetings, but refused to even look up from the podium while doing so. His anxiety worsened, his heart rate increased, and his palms sweated while leading the group. He began attending different AA meetings so that others would not recognize him and volunteer him to lead.

He adds that he feels comfortable meeting and dating women, since these exchanges are “scripted.” As he gets to know his partner better, however, Mr. I becomes more self-conscious.

Which of Mr. I’s symptoms would you address first: the depressive or the phobic?

Drs. Yu’s, Gordon’s, and Maguire’s observations

Based on Mr. I’s presentation, one might at first diagnose major depressive disorder, but chronic avoidance patterns differentiate his illness from an endogenous depression. Mr. I was diagnosed as having social phobia, a disorder that has been gaining attention among researchers.

A phobia is defined as an irrational fear that produces conscious avoidance of the feared subject, activity, or situation. The presence or anticipation of the phobic entity elicits severe distress, though the affected person usually recognizes that the reaction is excessive. DSM-IV defines social phobia as a strong, persisting fear of potentially embarrassing situations (Box).¹

Two peaks of onset have been described: one occurring before age 5, and the other between ages 11 and 17.² The mean age of onset has been reported to be 15.²

Box

DSM-IV describes two types of social phobia: generalized social phobia and performance phobia. Normal fear and shyness should be differentiated from social phobia. Medical conditions—including CNS tumors and cerebrovascular diseases—and drugs typically bring about neurologic and mental status symptoms that can confound the diagnosis.

Symptoms of other anxiety disorders, including panic disorder and agoraphobia, may mimic social phobia. Fear in social phobia is not present outside of, or in anticipation of, the feared situation. Social phobia also can be misdiagnosed as an avoidant personality, schizoid personality, or major depressive disorder.¹

At this point, one should consider diagnosing Mr. I with social phobia, as evinced by his excessive avoidance of social situations. Mr. I also recognizes that his avoidance is excessive and causes difficulty in his daily functioning.

Behavioral inhibition in childhood is suggested to be more common in children with parents who had panic disorder. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.^5-7’

First treatment: Pharmacotherapy and psychotherapy

Mr. I is interested in trying an antidepressant, but noted that about 6 years ago a brief course of a selective serotonin reuptake inhibitor led to difficulty sleeping and decreased libido and orgasm. He agrees to take bupropion SR, 100 mg/d, titrated after 2 weeks to 100 mg bid.

He also begins cognitive-behavioral and supportive therapy, during which he reveals that his pattern of avoidance took root in grade school, where he was often a quiet sidekick to the popular kids. During therapy, he describes visitations with his daughters, both of whom live with his ex-wife, as extremely difficult.

“I really don’t know what to say,” Mr. I says. “We often stare at each other during dessert, and I want to get it over with and go home.”

After 1 month, his bupropion SR is increased to 150 mg bid. One month later, his feelings of depression are under control. He sleeps well, no longer feels fatigued, and can concentrate. Still he isolates himself, fearing others’ disapproval. He has become more resistant to psychotherapy. “I know my patterns. I know what I do, but I can’t change it,” he says.

How would you treat Mr. I’s persistent social phobia? Would you switch his medications or augment existing ones? Does psychotherapy still have a role in treatment?

Drs. Yu’s, Gordon’s, and Maguire’s observations

Pharmacologic treatment of social phobia has spawned several neurochemical hypotheses. As beta-adrenergic antagonists have been proven efficacious in treating performance phobia, an adrenergic hypothesis suggests patients with performance phobia release more norepinephrine and epinephrine or are more sensitive to normal levels of these neuro-transmitters.⁸

The success of monoamine oxidase inhibitors in generalized social phobia suggests that dopamine plays a role in treating this form of the disorder. Central dopamine activity has been associated with positive emotions or extraversion.⁹

SSRIs have also demonstrated efficacy against generalized social phobia.¹⁰ Researchers have associated higher serotonin levels with increased social dominance¹¹ and suggest that abnormal dopamine and serotonin levels contribute to the disorder’s pathogenesis.

Current treatments include psychotherapy and pharmacotherapy, and studies suggest that a combination of the two may be more efficacious than either alone.⁸ Venlafaxine, phenelzine, buspirone, benzodiazepines, and SSRIs have all demonstrated effectiveness and tolerability in generalized social phobia. Beta-adrenergic receptor antagonists (e.g., atenolol, propranolol) are commonly administered to treat performance phobia shortly before exposure to the phobic stimulus.

An adequate time frame for psychopharmacologic treatment of social phobia has not been defined. In depression therapy, medications should be maintained for at least 4 to 5 weeks before considering the regimen unsuccessful.¹

While Mr. I’s depression responded well to bupropion SR, a medication whose mechanism involves dopamine and norepinephrine reuptake, use of a medication that augments his serotonin may further improve his condition.

Cognitive and behavioral therapies also are indicated for both generalized social phobia and performance phobia. These should be considered along with medication therapy for Mr. I to treat his social phobia and prevent a relapse.

Despite the available evidence, however, the course and prognosis of social phobia are not clear. Data are still forthcoming on this recently recognized disorder.

Further treatment: Another neurotransmitter

Again cautious of potential adverse sexual effects, Mr. I agrees to try mirtazapine, 30 mg at bedtime, in addition to bupropion SR. He initially complains of sedation and lowered energy, but is willing to continue the mirtazapine, hoping that it will help his social phobia.

Two months after starting mirtazapine, Mr. I is still fearful at work and home, and his relationship with his order. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.^5-7’ daughters has not improved. After another month, he reports that his sedation has resolved, but complains of increased fatigue and difficulty concentrating. He suspects that the bupropion SR has stopped working.

After another month, Mr. I self-discontinues the mirtazapine. Though he tries to participate in social situations, his anxiety has worsened. He goes to a country music club once a week but is afraid to ask anyone to dance.

Should you focus on Mr. I’s depression rather than his social phobia? If so, how do you change his treatment?

Drs. Yu’s, Gordon’s, and Maguire’s observations

The severity of Mr. I’s social phobia may be causing his depression. Both trials of bupropion SR and mirtazapine have been adequate for his depression but have not alleviated his social phobia.

Medications that affect gamma-aminobutyric acid (GABA) levels, specifically benzodiazepines, have not been tried. Benzodiazepines provide rapid relief with little risk in short-term treatment, but dependence/withdrawal risks increase greatly when given more than 4 to 6 months.⁸ Because of Mr. I’s chronic anxiety in social phobia and his history of alcoholism, benzodiazepines are not recommended.

The novel compound tiagabine has been shown to increase GABA in the synaptic cleft.¹² GABA increases chloride conduction through its ligand-gated channels, creating a potential antianxiety effect similar to that produced by benzodiazepines.^8,13,14 GAT-1, the predominant transporter, removes excess GABA.

Just as SSRIs inhibit serotonin reuptake and allow the neurotransmitter to act on its receptors to alleviate depression and anxiety, so does tiagabine inhibit GAT-1. Theoretically, tiagabine may relieve anxiety by increasing synaptic concentrations of GABA.

Tiagabine also has been shown to be well-tolerated without a known abuse or dependence potential.¹² Possible adverse effects include impaired concentration, somnolence, fatigue, nausea, and dizziness. To avoid adverse effects, slow titration (about 4 mg per week) is recommended.

Changing treatment: Looking up

Tiagabine, 4 mg at bedtime, is added to help with Mr. I’s anxiety; he is instructed to increase the dosage by 4 mg every 5 days in divided doses. He began to sense improvement during the second week, at 4 mg bid, and 2 weeks later his anxiety has been greatly reduced. He can now sit quietly with his co-workers during coffee breaks and has begun training a co-worker, which he never dared to attempt before. At this point, he was tolerating tiagabine at 8 mg bid.

One month later, tiagabine is increased to 16 mg bid. Mr. I has noticed mild dizziness with each dosage increase, but each time it subsided within a day. He has been maintained on 16 mg bid.

Saying that his anxiety is now well-controlled, Mr. I enjoys at least one dance each week at the country music club he frequents. One week later, he led an Alcoholics Anonymous meeting—while looking up to his audience for the first time. He continues these activities and his therapy sessions, which are geared toward developing stronger skills to minimize his anxiety. He is considering lowering his medication dosages (though he is wary of a possible relapse) and furthering his therapy.

Related resources

• Anxiety Disorders Association of America www.adaa.org
• National Institute of Mental Health: Phobias from NLM’s MEDLINEplus http://www.nlm.nih.gov/medlineplus/phobias.html

Author affiliations

Dr. Yu is a fellow in child and adolescent psychiatry, Dr. Gordon is a resident physician; and Dr. Maguire is assistant dean for continuing medical education, director of resident training, and associate clinical professor, department of psychiatry, University of California, Irvine.

Drug brand names

• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Mirtazapine • Remeron
• Phenelzine • Nardil
• Tiagabine • Gabitril
• Venlafaxine • Effexor

Disclosure

Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc., Novartis Pharmaceuticals Corp., and Pfizer Inc., and receives research/grant support from and serves as a consultant to Eli Lilly and Co.

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

Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly and Co., is on the speaker’s bureau of Pfizer Inc., and receives research/grant support from Forest Laboratories and GlaxoSmithKline.

History: Living in fear

Mr. I, 41, presents for an initial psychiatric evaluation. He saw a psychologist 8 years ago for a “mild depression,” which he described as a lack of motivation and difficulty concentrating. His mood has been chronically “flat” for the last 10 years. He complains of poor energy and decreased sleep because of irregular work hours, and admits to using over-the-counter caffeine pills to help him function.

The patient denies suicidal ideations, symptoms of guilt, psychotic symptoms, or crying spells, but has a history of alcoholism and cocaine abuse. (He has been sober for 5 years.) Significant recent stressors include a recent breakup with his girlfriend, which he adds “really hasn’t bothered me at all.”

Mr. I has been increasingly avoiding social situations. Though he denies having panic attacks, interaction with other people triggers shortness of breath and chest tight-ness, especially when speaking in public to strangers.

The fear of what others might think of him is dominating Mr. I’s life. For example, he would like to console a housemate whose mother died, but because he is afraid of how the friend will react, Mr. I has not approached him. He adds that he goes out of his way to avoid contact with his co-workers, working irregular hours and eating his lunch in his car rather than the office lounge—even in inclement weather.

Mr. I does attend Alcoholic Anonymous meetings, but often sits toward the back. He had led some meetings, but refused to even look up from the podium while doing so. His anxiety worsened, his heart rate increased, and his palms sweated while leading the group. He began attending different AA meetings so that others would not recognize him and volunteer him to lead.

He adds that he feels comfortable meeting and dating women, since these exchanges are “scripted.” As he gets to know his partner better, however, Mr. I becomes more self-conscious.

Which of Mr. I’s symptoms would you address first: the depressive or the phobic?

Drs. Yu’s, Gordon’s, and Maguire’s observations

Based on Mr. I’s presentation, one might at first diagnose major depressive disorder, but chronic avoidance patterns differentiate his illness from an endogenous depression. Mr. I was diagnosed as having social phobia, a disorder that has been gaining attention among researchers.

A phobia is defined as an irrational fear that produces conscious avoidance of the feared subject, activity, or situation. The presence or anticipation of the phobic entity elicits severe distress, though the affected person usually recognizes that the reaction is excessive. DSM-IV defines social phobia as a strong, persisting fear of potentially embarrassing situations (Box).¹

Two peaks of onset have been described: one occurring before age 5, and the other between ages 11 and 17.² The mean age of onset has been reported to be 15.²

Box

DSM-IV describes two types of social phobia: generalized social phobia and performance phobia. Normal fear and shyness should be differentiated from social phobia. Medical conditions—including CNS tumors and cerebrovascular diseases—and drugs typically bring about neurologic and mental status symptoms that can confound the diagnosis.

Symptoms of other anxiety disorders, including panic disorder and agoraphobia, may mimic social phobia. Fear in social phobia is not present outside of, or in anticipation of, the feared situation. Social phobia also can be misdiagnosed as an avoidant personality, schizoid personality, or major depressive disorder.¹

At this point, one should consider diagnosing Mr. I with social phobia, as evinced by his excessive avoidance of social situations. Mr. I also recognizes that his avoidance is excessive and causes difficulty in his daily functioning.

Behavioral inhibition in childhood is suggested to be more common in children with parents who had panic disorder. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.^5-7’

First treatment: Pharmacotherapy and psychotherapy

Mr. I is interested in trying an antidepressant, but noted that about 6 years ago a brief course of a selective serotonin reuptake inhibitor led to difficulty sleeping and decreased libido and orgasm. He agrees to take bupropion SR, 100 mg/d, titrated after 2 weeks to 100 mg bid.

He also begins cognitive-behavioral and supportive therapy, during which he reveals that his pattern of avoidance took root in grade school, where he was often a quiet sidekick to the popular kids. During therapy, he describes visitations with his daughters, both of whom live with his ex-wife, as extremely difficult.

“I really don’t know what to say,” Mr. I says. “We often stare at each other during dessert, and I want to get it over with and go home.”

After 1 month, his bupropion SR is increased to 150 mg bid. One month later, his feelings of depression are under control. He sleeps well, no longer feels fatigued, and can concentrate. Still he isolates himself, fearing others’ disapproval. He has become more resistant to psychotherapy. “I know my patterns. I know what I do, but I can’t change it,” he says.

How would you treat Mr. I’s persistent social phobia? Would you switch his medications or augment existing ones? Does psychotherapy still have a role in treatment?

Drs. Yu’s, Gordon’s, and Maguire’s observations

Pharmacologic treatment of social phobia has spawned several neurochemical hypotheses. As beta-adrenergic antagonists have been proven efficacious in treating performance phobia, an adrenergic hypothesis suggests patients with performance phobia release more norepinephrine and epinephrine or are more sensitive to normal levels of these neuro-transmitters.⁸

The success of monoamine oxidase inhibitors in generalized social phobia suggests that dopamine plays a role in treating this form of the disorder. Central dopamine activity has been associated with positive emotions or extraversion.⁹

SSRIs have also demonstrated efficacy against generalized social phobia.¹⁰ Researchers have associated higher serotonin levels with increased social dominance¹¹ and suggest that abnormal dopamine and serotonin levels contribute to the disorder’s pathogenesis.

Current treatments include psychotherapy and pharmacotherapy, and studies suggest that a combination of the two may be more efficacious than either alone.⁸ Venlafaxine, phenelzine, buspirone, benzodiazepines, and SSRIs have all demonstrated effectiveness and tolerability in generalized social phobia. Beta-adrenergic receptor antagonists (e.g., atenolol, propranolol) are commonly administered to treat performance phobia shortly before exposure to the phobic stimulus.

An adequate time frame for psychopharmacologic treatment of social phobia has not been defined. In depression therapy, medications should be maintained for at least 4 to 5 weeks before considering the regimen unsuccessful.¹

While Mr. I’s depression responded well to bupropion SR, a medication whose mechanism involves dopamine and norepinephrine reuptake, use of a medication that augments his serotonin may further improve his condition.

Cognitive and behavioral therapies also are indicated for both generalized social phobia and performance phobia. These should be considered along with medication therapy for Mr. I to treat his social phobia and prevent a relapse.

Despite the available evidence, however, the course and prognosis of social phobia are not clear. Data are still forthcoming on this recently recognized disorder.

Further treatment: Another neurotransmitter

Again cautious of potential adverse sexual effects, Mr. I agrees to try mirtazapine, 30 mg at bedtime, in addition to bupropion SR. He initially complains of sedation and lowered energy, but is willing to continue the mirtazapine, hoping that it will help his social phobia.

Two months after starting mirtazapine, Mr. I is still fearful at work and home, and his relationship with his order. Generalized fear may manifest later as excessive shyness. Several studies have linked childhood behavior inhibition to social phobia.^5-7’ daughters has not improved. After another month, he reports that his sedation has resolved, but complains of increased fatigue and difficulty concentrating. He suspects that the bupropion SR has stopped working.

After another month, Mr. I self-discontinues the mirtazapine. Though he tries to participate in social situations, his anxiety has worsened. He goes to a country music club once a week but is afraid to ask anyone to dance.

Should you focus on Mr. I’s depression rather than his social phobia? If so, how do you change his treatment?

Drs. Yu’s, Gordon’s, and Maguire’s observations

The severity of Mr. I’s social phobia may be causing his depression. Both trials of bupropion SR and mirtazapine have been adequate for his depression but have not alleviated his social phobia.

Medications that affect gamma-aminobutyric acid (GABA) levels, specifically benzodiazepines, have not been tried. Benzodiazepines provide rapid relief with little risk in short-term treatment, but dependence/withdrawal risks increase greatly when given more than 4 to 6 months.⁸ Because of Mr. I’s chronic anxiety in social phobia and his history of alcoholism, benzodiazepines are not recommended.

The novel compound tiagabine has been shown to increase GABA in the synaptic cleft.¹² GABA increases chloride conduction through its ligand-gated channels, creating a potential antianxiety effect similar to that produced by benzodiazepines.^8,13,14 GAT-1, the predominant transporter, removes excess GABA.

Just as SSRIs inhibit serotonin reuptake and allow the neurotransmitter to act on its receptors to alleviate depression and anxiety, so does tiagabine inhibit GAT-1. Theoretically, tiagabine may relieve anxiety by increasing synaptic concentrations of GABA.

Tiagabine also has been shown to be well-tolerated without a known abuse or dependence potential.¹² Possible adverse effects include impaired concentration, somnolence, fatigue, nausea, and dizziness. To avoid adverse effects, slow titration (about 4 mg per week) is recommended.

Changing treatment: Looking up

Tiagabine, 4 mg at bedtime, is added to help with Mr. I’s anxiety; he is instructed to increase the dosage by 4 mg every 5 days in divided doses. He began to sense improvement during the second week, at 4 mg bid, and 2 weeks later his anxiety has been greatly reduced. He can now sit quietly with his co-workers during coffee breaks and has begun training a co-worker, which he never dared to attempt before. At this point, he was tolerating tiagabine at 8 mg bid.

One month later, tiagabine is increased to 16 mg bid. Mr. I has noticed mild dizziness with each dosage increase, but each time it subsided within a day. He has been maintained on 16 mg bid.

Saying that his anxiety is now well-controlled, Mr. I enjoys at least one dance each week at the country music club he frequents. One week later, he led an Alcoholics Anonymous meeting—while looking up to his audience for the first time. He continues these activities and his therapy sessions, which are geared toward developing stronger skills to minimize his anxiety. He is considering lowering his medication dosages (though he is wary of a possible relapse) and furthering his therapy.

Related resources

• Anxiety Disorders Association of America www.adaa.org
• National Institute of Mental Health: Phobias from NLM’s MEDLINEplus http://www.nlm.nih.gov/medlineplus/phobias.html

Author affiliations

Dr. Yu is a fellow in child and adolescent psychiatry, Dr. Gordon is a resident physician; and Dr. Maguire is assistant dean for continuing medical education, director of resident training, and associate clinical professor, department of psychiatry, University of California, Irvine.

Drug brand names

• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Mirtazapine • Remeron
• Phenelzine • Nardil
• Tiagabine • Gabitril
• Venlafaxine • Effexor

Disclosure

Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc., Novartis Pharmaceuticals Corp., and Pfizer Inc., and receives research/grant support from and serves as a consultant to Eli Lilly and Co.

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

Dr. Maguire reports that he receives research/grant support from, serves as a consultant to, and is on the speaker’s bureau of Eli Lilly and Co., is on the speaker’s bureau of Pfizer Inc., and receives research/grant support from Forest Laboratories and GlaxoSmithKline.