Current Psychiatry

The article, “For women only: Hormones may prevent addiction relapse” (Current Psychiatry, August 2006) contained an error on page 42.

Reference 7 supports the statement that “higher stress responsiveness is associated with increased cocaine craving,” but reference 8 shows that—unlike in cocaine addiction—lower HPA axis responsiveness in alcoholics is associated with an increased risk of relapse.

The article, “For women only: Hormones may prevent addiction relapse” (Current Psychiatry, August 2006) contained an error on page 42.

Reference 7 supports the statement that “higher stress responsiveness is associated with increased cocaine craving,” but reference 8 shows that—unlike in cocaine addiction—lower HPA axis responsiveness in alcoholics is associated with an increased risk of relapse.

The article, “For women only: Hormones may prevent addiction relapse” (Current Psychiatry, August 2006) contained an error on page 42.

Reference 7 supports the statement that “higher stress responsiveness is associated with increased cocaine craving,” but reference 8 shows that—unlike in cocaine addiction—lower HPA axis responsiveness in alcoholics is associated with an increased risk of relapse.

I found Dr. Richard C. Christensen’s article (“‘Prescribing’ behavioral and lifestyle changes,” Current Psychiatry, July 2006) very useful. I am a therapist, but I think it is important for physicians to remember that the power of the prescription pad can go beyond prescribing medications. Thank you for this insightful article.

Richard Cloyd
Dandridge, TN

I found Dr. Richard C. Christensen’s article (“‘Prescribing’ behavioral and lifestyle changes,” Current Psychiatry, July 2006) very useful. I am a therapist, but I think it is important for physicians to remember that the power of the prescription pad can go beyond prescribing medications. Thank you for this insightful article.

Richard Cloyd
Dandridge, TN

I found Dr. Richard C. Christensen’s article (“‘Prescribing’ behavioral and lifestyle changes,” Current Psychiatry, July 2006) very useful. I am a therapist, but I think it is important for physicians to remember that the power of the prescription pad can go beyond prescribing medications. Thank you for this insightful article.

Richard Cloyd
Dandridge, TN

I’m glad to see Dr. Henry Nasrallah at the helm of Current Psychiatry. It is one of the few journals I read cover to cover. Although it does not publish original research, the journal interprets important studies like CATIE in a way that is interesting and useable.

Robert Karp, MD
Medical director, vice president
Maumee Valley Guidance Center
Defiance, OH

I’m glad to see Dr. Henry Nasrallah at the helm of Current Psychiatry. It is one of the few journals I read cover to cover. Although it does not publish original research, the journal interprets important studies like CATIE in a way that is interesting and useable.

Robert Karp, MD
Medical director, vice president
Maumee Valley Guidance Center
Defiance, OH

I’m glad to see Dr. Henry Nasrallah at the helm of Current Psychiatry. It is one of the few journals I read cover to cover. Although it does not publish original research, the journal interprets important studies like CATIE in a way that is interesting and useable.

Robert Karp, MD
Medical director, vice president
Maumee Valley Guidance Center
Defiance, OH

“Cases That Test Your Skills: Is it anxiety, depression, or bipolar disorder?” (Current Psychiatry, August 2006) succinctly captures a common problem found in clinical practice. The authors’ methodical and meticulous teasing out of the differential diagnosis was based on clinical findings rather than a hunch. Various tables and the authors’ method to clarify the diagnosis and treat the patient effectively were helpful.

I am curious why the authors did not consider whether clonazepam or other benzodiazepines—with or without buspirone—would have resolved the patient’s anxiety faster than buspirone alone. According to the article, clonazepam had not been tried during the patient’s previous treatments and she did not have a history of substance abuse.

Vasudev N. Makhija, MD
Linden, NJ

Dr. Singh responds

Besides my preference to use nonbenzodiazepine drugs as a first-line treatment for anxiety disorders, medications like clonazepam^1,2 act as antianxiety and mood stabilizing agents. If the patient had responded to clonazepam, it would not have been clear whether bipolar disorder or anxiety disorder was the correct diagnosis. We decided to use buspirone because it is an antianxiety agent that does not affect mood.

Tanvir Singh, MD
Assistant professor of psychiatry
University of Toledo, Health Science Campus
Toledo, OH

“Cases That Test Your Skills: Is it anxiety, depression, or bipolar disorder?” (Current Psychiatry, August 2006) succinctly captures a common problem found in clinical practice. The authors’ methodical and meticulous teasing out of the differential diagnosis was based on clinical findings rather than a hunch. Various tables and the authors’ method to clarify the diagnosis and treat the patient effectively were helpful.

I am curious why the authors did not consider whether clonazepam or other benzodiazepines—with or without buspirone—would have resolved the patient’s anxiety faster than buspirone alone. According to the article, clonazepam had not been tried during the patient’s previous treatments and she did not have a history of substance abuse.

Vasudev N. Makhija, MD
Linden, NJ

Dr. Singh responds

Besides my preference to use nonbenzodiazepine drugs as a first-line treatment for anxiety disorders, medications like clonazepam^1,2 act as antianxiety and mood stabilizing agents. If the patient had responded to clonazepam, it would not have been clear whether bipolar disorder or anxiety disorder was the correct diagnosis. We decided to use buspirone because it is an antianxiety agent that does not affect mood.

Tanvir Singh, MD
Assistant professor of psychiatry
University of Toledo, Health Science Campus
Toledo, OH

“Cases That Test Your Skills: Is it anxiety, depression, or bipolar disorder?” (Current Psychiatry, August 2006) succinctly captures a common problem found in clinical practice. The authors’ methodical and meticulous teasing out of the differential diagnosis was based on clinical findings rather than a hunch. Various tables and the authors’ method to clarify the diagnosis and treat the patient effectively were helpful.

I am curious why the authors did not consider whether clonazepam or other benzodiazepines—with or without buspirone—would have resolved the patient’s anxiety faster than buspirone alone. According to the article, clonazepam had not been tried during the patient’s previous treatments and she did not have a history of substance abuse.

Vasudev N. Makhija, MD
Linden, NJ

Dr. Singh responds

Besides my preference to use nonbenzodiazepine drugs as a first-line treatment for anxiety disorders, medications like clonazepam^1,2 act as antianxiety and mood stabilizing agents. If the patient had responded to clonazepam, it would not have been clear whether bipolar disorder or anxiety disorder was the correct diagnosis. We decided to use buspirone because it is an antianxiety agent that does not affect mood.

Tanvir Singh, MD
Assistant professor of psychiatry
University of Toledo, Health Science Campus
Toledo, OH

There is much more to dopamine than schizophrenia and Parkinson’s disease. Research has discovered a fascinating array of dopamine functions, some as triggers for neuropsychiatric disorders and others critical for healthy living.

Here’s a quiz; how many of the following functions of dopamine’s six receptors and four pathways do you know?

Motor coordination. Most of us take for granted moving or handling objects, thanks to normal dopamine levels in our nigrostriatal tracts. However, one look at a person afflicted with Parkinson’s disease trying to walk or hold a cup of coffee should make us grateful to dopamine for freedom of movement.

Abnormal vs. reality testing. Normal dopamine activity in the mesolimbic tract is vital to maintaining a healthy, adaptive awareness of our surroundings. Persons with abnormally heightened dopamine activity in the medial temporal region—for example, abusers of dopamine agonists such as methamphetamine (see "The 'meth' epidemic")—can be tormented by ideas of reference and delusions about neutral environmental stimuli.

Reward and pleasure. It is hard to imagine life without experiencing fun doing pleasurable activities. So give credit to dopamine in the ventral striatum for all the activities you enjoy, such as playing golf, watching an opera, or socializing with good friends. The dopamine receptor gene has been referred to as “the reward gene.”

Cognition and decision-making. Critical cognitive tasks such as memory, attention, and executive functions depend on an intact mesocortical dopamine pathway. Going to school or holding a job is impossible if mesocortical dopamine is deficient, which is why persons with schizophrenia become disabled.

Placebo effect. Psychiatrists appreciate the high placebo response rates associated with treating depression, anxiety, insomnia, or pain. Research implicates the release of dopamine in the reward pathways that probably are involved in alleviating psychiatric and physical symptoms. Even patients with Parkinson’s disease receiving sham deep brain stimulation or striatal tissue transplants in controlled clinical trials may improve initially because of dopamine release.

Depression. Dopamine is a monoamine that modulates mood, and a decrement in dopamine leads to dysphoria or major depression. Dopamine deficiency states such as Parkinson’s disease are frequently associated with depression and can be treated with dopaminergic antidepressants.

Social defeat. People—and animals as well—can develop permanent aversion to social contact if exposed to unrelenting abuse and violence. Mesolimbic dopamine pathways are implicated in this syndrome of “social defeat,” which can be reversed by chronic administration of antidepressants.

Alcohol dependence. Dopamine receptor dysfunction has been linked with a propensity to abuse alcohol and to reduced sensitivity to reward. The mesolimbic dopamine pathway appears to be critical for experiencing pleasure from abused drugs and is thought to be a common denominator for addictions and drug-seeking behavior.

Hypersexuality. When levodopa [L-dopa] was first used to treat Parkinson’s disease, one of its earliest side effects was increased sexual drive. This effect has been observed with other dopamine agonists and is attributed to potentiation of reward pathways that reinforce pleasurable activities. Other factors also may be involved, as in impulse control disorders.

Pathologic gambling. Treating Parkinson’s disease with dopamine agonists has been associated with an increase in pathologic gambling, an impulse control disorder. The incidence approaches 10%.

Compulsive shopping. Excessive, inappropriate buying is another impulse control disorder that emerges during dopamine agonist therapy.

ADHD. A cortical/frontal dopamine deficit is believed important in the pathophysiology of attention-deficit/hyperactivity disorder. ADHD symptoms can be alleviated with dopamine agonists (stimulants).

Dopamine can enhance health but also disrupt movement, mood, and behavior and lead to neuropsychiatric disorders. This neurotransmitter can reward or torment us. I invite you to send me e-mail ([email protected]) to comment on the 12 functions I’ve listed above or on other disorders you have observed that result from excessive or deficient dopamine activity.

P.S. Three days after I wrote this editorial, researchers announced another potential role for dopamine: regulating the sleep-wake cycle.¹ Excess dopamine in mice allowed rapid-eye movement (REM) sleep (i.e., dreaming) to intrude on wakefulness! This may explain the dreamlike hallucinations in schizophrenia or L-dopa psychosis. Mice with depleted dopamine stopped having REM, even during sleep, but injecting them with D2 receptor agonists restored REM.

There is much more to dopamine than schizophrenia and Parkinson’s disease. Research has discovered a fascinating array of dopamine functions, some as triggers for neuropsychiatric disorders and others critical for healthy living.

Here’s a quiz; how many of the following functions of dopamine’s six receptors and four pathways do you know?

Motor coordination. Most of us take for granted moving or handling objects, thanks to normal dopamine levels in our nigrostriatal tracts. However, one look at a person afflicted with Parkinson’s disease trying to walk or hold a cup of coffee should make us grateful to dopamine for freedom of movement.

Abnormal vs. reality testing. Normal dopamine activity in the mesolimbic tract is vital to maintaining a healthy, adaptive awareness of our surroundings. Persons with abnormally heightened dopamine activity in the medial temporal region—for example, abusers of dopamine agonists such as methamphetamine (see "The 'meth' epidemic")—can be tormented by ideas of reference and delusions about neutral environmental stimuli.

Reward and pleasure. It is hard to imagine life without experiencing fun doing pleasurable activities. So give credit to dopamine in the ventral striatum for all the activities you enjoy, such as playing golf, watching an opera, or socializing with good friends. The dopamine receptor gene has been referred to as “the reward gene.”

Cognition and decision-making. Critical cognitive tasks such as memory, attention, and executive functions depend on an intact mesocortical dopamine pathway. Going to school or holding a job is impossible if mesocortical dopamine is deficient, which is why persons with schizophrenia become disabled.

Placebo effect. Psychiatrists appreciate the high placebo response rates associated with treating depression, anxiety, insomnia, or pain. Research implicates the release of dopamine in the reward pathways that probably are involved in alleviating psychiatric and physical symptoms. Even patients with Parkinson’s disease receiving sham deep brain stimulation or striatal tissue transplants in controlled clinical trials may improve initially because of dopamine release.

Depression. Dopamine is a monoamine that modulates mood, and a decrement in dopamine leads to dysphoria or major depression. Dopamine deficiency states such as Parkinson’s disease are frequently associated with depression and can be treated with dopaminergic antidepressants.

Social defeat. People—and animals as well—can develop permanent aversion to social contact if exposed to unrelenting abuse and violence. Mesolimbic dopamine pathways are implicated in this syndrome of “social defeat,” which can be reversed by chronic administration of antidepressants.

Alcohol dependence. Dopamine receptor dysfunction has been linked with a propensity to abuse alcohol and to reduced sensitivity to reward. The mesolimbic dopamine pathway appears to be critical for experiencing pleasure from abused drugs and is thought to be a common denominator for addictions and drug-seeking behavior.

Hypersexuality. When levodopa [L-dopa] was first used to treat Parkinson’s disease, one of its earliest side effects was increased sexual drive. This effect has been observed with other dopamine agonists and is attributed to potentiation of reward pathways that reinforce pleasurable activities. Other factors also may be involved, as in impulse control disorders.

Pathologic gambling. Treating Parkinson’s disease with dopamine agonists has been associated with an increase in pathologic gambling, an impulse control disorder. The incidence approaches 10%.

Compulsive shopping. Excessive, inappropriate buying is another impulse control disorder that emerges during dopamine agonist therapy.

ADHD. A cortical/frontal dopamine deficit is believed important in the pathophysiology of attention-deficit/hyperactivity disorder. ADHD symptoms can be alleviated with dopamine agonists (stimulants).

Dopamine can enhance health but also disrupt movement, mood, and behavior and lead to neuropsychiatric disorders. This neurotransmitter can reward or torment us. I invite you to send me e-mail ([email protected]) to comment on the 12 functions I’ve listed above or on other disorders you have observed that result from excessive or deficient dopamine activity.

P.S. Three days after I wrote this editorial, researchers announced another potential role for dopamine: regulating the sleep-wake cycle.¹ Excess dopamine in mice allowed rapid-eye movement (REM) sleep (i.e., dreaming) to intrude on wakefulness! This may explain the dreamlike hallucinations in schizophrenia or L-dopa psychosis. Mice with depleted dopamine stopped having REM, even during sleep, but injecting them with D2 receptor agonists restored REM.

There is much more to dopamine than schizophrenia and Parkinson’s disease. Research has discovered a fascinating array of dopamine functions, some as triggers for neuropsychiatric disorders and others critical for healthy living.

Here’s a quiz; how many of the following functions of dopamine’s six receptors and four pathways do you know?

Motor coordination. Most of us take for granted moving or handling objects, thanks to normal dopamine levels in our nigrostriatal tracts. However, one look at a person afflicted with Parkinson’s disease trying to walk or hold a cup of coffee should make us grateful to dopamine for freedom of movement.

Abnormal vs. reality testing. Normal dopamine activity in the mesolimbic tract is vital to maintaining a healthy, adaptive awareness of our surroundings. Persons with abnormally heightened dopamine activity in the medial temporal region—for example, abusers of dopamine agonists such as methamphetamine (see "The 'meth' epidemic")—can be tormented by ideas of reference and delusions about neutral environmental stimuli.

Reward and pleasure. It is hard to imagine life without experiencing fun doing pleasurable activities. So give credit to dopamine in the ventral striatum for all the activities you enjoy, such as playing golf, watching an opera, or socializing with good friends. The dopamine receptor gene has been referred to as “the reward gene.”

Cognition and decision-making. Critical cognitive tasks such as memory, attention, and executive functions depend on an intact mesocortical dopamine pathway. Going to school or holding a job is impossible if mesocortical dopamine is deficient, which is why persons with schizophrenia become disabled.

Placebo effect. Psychiatrists appreciate the high placebo response rates associated with treating depression, anxiety, insomnia, or pain. Research implicates the release of dopamine in the reward pathways that probably are involved in alleviating psychiatric and physical symptoms. Even patients with Parkinson’s disease receiving sham deep brain stimulation or striatal tissue transplants in controlled clinical trials may improve initially because of dopamine release.

Depression. Dopamine is a monoamine that modulates mood, and a decrement in dopamine leads to dysphoria or major depression. Dopamine deficiency states such as Parkinson’s disease are frequently associated with depression and can be treated with dopaminergic antidepressants.

Social defeat. People—and animals as well—can develop permanent aversion to social contact if exposed to unrelenting abuse and violence. Mesolimbic dopamine pathways are implicated in this syndrome of “social defeat,” which can be reversed by chronic administration of antidepressants.

Alcohol dependence. Dopamine receptor dysfunction has been linked with a propensity to abuse alcohol and to reduced sensitivity to reward. The mesolimbic dopamine pathway appears to be critical for experiencing pleasure from abused drugs and is thought to be a common denominator for addictions and drug-seeking behavior.

Hypersexuality. When levodopa [L-dopa] was first used to treat Parkinson’s disease, one of its earliest side effects was increased sexual drive. This effect has been observed with other dopamine agonists and is attributed to potentiation of reward pathways that reinforce pleasurable activities. Other factors also may be involved, as in impulse control disorders.

Pathologic gambling. Treating Parkinson’s disease with dopamine agonists has been associated with an increase in pathologic gambling, an impulse control disorder. The incidence approaches 10%.

Compulsive shopping. Excessive, inappropriate buying is another impulse control disorder that emerges during dopamine agonist therapy.

ADHD. A cortical/frontal dopamine deficit is believed important in the pathophysiology of attention-deficit/hyperactivity disorder. ADHD symptoms can be alleviated with dopamine agonists (stimulants).

Dopamine can enhance health but also disrupt movement, mood, and behavior and lead to neuropsychiatric disorders. This neurotransmitter can reward or torment us. I invite you to send me e-mail ([email protected]) to comment on the 12 functions I’ve listed above or on other disorders you have observed that result from excessive or deficient dopamine activity.

P.S. Three days after I wrote this editorial, researchers announced another potential role for dopamine: regulating the sleep-wake cycle.¹ Excess dopamine in mice allowed rapid-eye movement (REM) sleep (i.e., dreaming) to intrude on wakefulness! This may explain the dreamlike hallucinations in schizophrenia or L-dopa psychosis. Mice with depleted dopamine stopped having REM, even during sleep, but injecting them with D2 receptor agonists restored REM.

History: a ‘negative’ view

Mr. J, a 50-year-old native of Fiji, has had depression and substance abuse disorder for more than 10 years, marked by irritability, poor sleep, hopelessness, and suicidality. He also suffered a traumatic brain injury in the military 25 years ago.

Police bring Mr. J to the ER after they find him wandering near traffic and speaking incoherently. His feet and hands jerk on the way to the hospital, leading police to suspect that Mr. J has suffered a grand mal seizure.

In the ER, Mr. J appears confused, has visual hallucinations, and moves his hands and feet involuntarily. His head and arms move erratically during the ER psychiatrist’s interview, and he says that his pelvis is arching forward and preventing him from walking steadily. The day before, he says, he saw frightening “visions” of a being who looked “like a photo negative.”

Mr. J has been seeing an outpatient psychiatrist, who has prescribed citalopram, 40 mg/d, for depression and clonazepam, 1 mg three times daily, for related anxiety symptoms.

The patient is disoriented and inattentive during the mental status examination. His cognitive deficits fluctuate in severity; at times he is aware of his surroundings, then suddenly loses this awareness.

Vital signs are stable. Physical exam shows Mr. J is approximately 30 lb underweight (97 lb) with a body mass index of 16.9 kg/m²—nearly 2 kg/m² below normal. He says he has been skipping meals because of poor appetite. He also has strikingly lizard-like, scaly skin.

Urine drug screen shows no signs of recent alcohol or substance abuse. Complete metabolic profile shows elevated liver enzymes, suggesting alcohol or illicit substance toxicity, medication toxicity, hepatitis, thyroid disorder, muscle disease, or a rare liver condition. EEG shows mild encephalopathy but no ictal activity.

poll here

The authors’ observations

Our psychiatric differential diagnosis is broad:

• visual and auditory hallucinations are concurrent in numerous disorders, including schizophrenia and depression
  
• visual hallucinations alone suggest dementia, delirium, or psychosis resulting from a medical condition, medication, or substance(s) of abuse¹
  
• Mr. J’s past head injury increases his risk of dementia and delirium
  
• his abrupt symptom onset and inattention suggest delirium.
  

Choreoathetosis can result from:

• medications such as stimulants and levodopa
  
• toxins
  
• systemic diseases such as systemic lupus erythematosus, thyrotoxicosis, or stroke
  
• degenerative brain diseases such as Huntington’s disease
  
• or focal brain diseases such as tumors.²
  

Although the test results narrow the differential diagnosis, we still have to consider numerous medical conditions that can cause delirium, such as trauma, cerebral vascular accident, intracerebral masses, CNS infection, and inflammatory disease.

poll here

History: collateral contributions

We refer Mr. J for lumbar puncture to rule out CNS infection and MRI to rule out tumor, abscess, or other structural brain abnormalities that could cause seizure. Results are unremarkable.

We then speak with Mr. J’s outpatient psychiatrist, who reports that Mr. J has had no residual cognitive impairment from his head injury. She adds, though, that he often develops cognitive problems after consuming large amounts of a traditional South Pacific beverage containing kava (Piper methysticum). She explains that Mr. J socializes with fellow Fijians who drink kava at gatherings, and that he often drinks kava to excess. She attributes his dry, scaly skin to excessive kava use.

Upon questioning, Mr. J says he consumes about a half-pound of kava root per day. He says he uses the root to make a tea-like beverage that, like alcohol, induces euphoria and relaxation. He says he began doing this in his youth back in Fiji, and now drinks “many cups” of kava per day.

Mr. J states that his current episode of strange movements and visual hallucinations began hours after he drank several cups of kava the day before police brought him to the ER. He considers his new psychiatric symptoms Jesus’ punishment for drinking kava.

The authors’ observations

Mr. J’s persecutory delusions suggest that he does not fully associate his symptoms with excessive kava use, but his abnormal movements, weight loss, skin changes, liver function abnormalities, and mental status changes are known adverse effects of kava.³ We diagnose substance-induced delirium rather than substance intoxication or substance-induced psychosis because:

• Mr. J’s cognitive symptoms are more severe than those caused by kava intoxication
  
• his psychotic symptoms occur only when he is delirious
  
• his disturbed consciousness, cognitive, and perceptual disturbances and the temporal relationship between symptom onset and massive kava use match DSM-IV-TR criteria for substance-induced delirium.⁴
  

Being aware of cultural customs and beliefs in your practice area can alert you to herbal substance use in various populations, such as kava by patients from the South Pacific or echinacea, goldenseal, and burdock by some Native Americans (see Related resources).

Medicinal use. Patients often use kava and other herbal supplements—including fatty acids, ginkgo biloba, ginseng, St. John’s wort, valerian, and others—with or instead of prescription drugs to alleviate psychiatric symptoms. Complementary and alternative medicine practitioners use kava to treat anxiety, for example (Box).

Anxiety and depression are among the most common reasons persons seek complementary or alternative treatment. In a national survey, 57% of respondents who suffered “anxiety attacks” and 54% of those with “severe depression” reported using such therapies.⁸ Nearly 1 in 5 persons who take prescription drugs also take herbs and/or high-dose vitamin supplements.⁹

Herbal products have been shown to cause adverse effects (Table 1).¹⁰ Kava, for example, has been associated with hepatotoxicity, dermopathy, movement disorders, GI disturbance, and weight loss. Standardized extracts such as capsules and tinctures appear more likely to cause adverse effects than traditional extractions, such as a beverage made by infusing kava root.⁵

Kava toxicity has been reported among heavy users. Although the dosage at which kava becomes dangerous is unknown, the FDA recommends that users not exceed typical dosages (50 to 280 mg/d) and use kava only under a physician’s supervision.¹¹

Also, interactions between herbal products and allopathic medications can cause substantial morbidity (Table 2). St. John’s wort, for example, can lead to serotonin syndrome when combined with selective serotonin reuptake inhibitors (SSRIs)¹² and can reduce blood levels of psychotropics metabolized by the cytochrome P-450 3A4 isoenzyme, such as alprazolam and carbamazepine.

Mr. J combined kava with clonazepam. Both substances affect gamma-aminobutyric (GABA) receptors, increasing the risk of sedation by depressing the CNS.

Table 1

Possible adverse effects of herbal supplements
used for psychiatric symptoms

Potential adverse interactions between psychotropics and complementary/alternative medications

Ask about alternative medicine use

According to a national survey,¹³ many patients do not tell allopathic physicians they are using complementary or alternative medications because:

• “It wasn’t important for the doctor to know.”
  
• “The doctor never asked.”
  
• “It was none of the doctor’s business.”
  
• “The doctor would not understand.”
  
• or “The doctor would disapprove or discourage CAM use.”
  

• routinely question patients about use of alternative therapies
  
• discuss safety and efficacy of commonly used alternative treatments
  
• discuss merits of alternative treatments
  
• provide information on the effectiveness and risks of various treatments
  
• learn about alternative therapies by consulting the Physicians’ Desk Reference (PDR) for Herbal Medicines or similar references
  
• help patients make decisions about alternative treatments, such as finding a qualified, licensed alternative provider.
  

Treatment: quick resolution

We admit Mr. J to the inpatient psychiatry unit. There, we continue his outpatient prescription medications at the same dosages and block access to nonprescription substances. His symptoms begin to improve during the first day of hospitalization. His choreoathetosis, hallucinations, and confusion resolve within 48 hours, and he is medically stable.

We discharge Mr. J after 2 days and continue citalopram and clonazepam at the same dosages.

The authors’ observations

Kava reaches peak plasma levels 1.8 hours after oral dosing and has a short (9-hour) elimination half-life. As a result, kava intoxication symptoms tend to resolve rapidly, as in Mr. J’s case.

Although Mr. J is medically stable, liver damage associated with kava use can be irreversible, prompting some European countries to ban its sale. Make sure patients who report kava use are aware of its hepatotoxicity risk.

Follow-up: kicking the kava habit

Two weeks after Mr. J’s discharge, his psychiatrist notes that his mental status has returned to baseline and that his skin has improved dramatically. The patient is following his citalopram and clonazepam regimen, and he seems more aware of kava’s potential adverse effects.

Mr. J reports that he has not consumed kava since his hospitalization. He has been eating four meals per day and has gained 9 lb. He is pleased with his improved appetite and is motivated to continue abstaining from kava.

Related resources

• National Center for Complementary and Alternative Medicine. http://nccam.nih.gov.
  
• Physicians Desk Reference (PDR) for herbal medicines, 3rd ed. Montvale, NJ: Thomson PDR; 2004.
  
• Ernst E, Pittler MH, Stevinson C, et al. The desktop guide to complementary and alternative medicine. Edinburgh, UK: Mosby; 2001.
  

• Alprazolam • Xanax
  
• Buspirone • BuSpar
  
• Carbamazepine • Equetro, others
  
• Carbidopa • Lodosyn
  
• Citalopram • Celexa
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Trazodone • Desyrel
  

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

History: a ‘negative’ view

Mr. J, a 50-year-old native of Fiji, has had depression and substance abuse disorder for more than 10 years, marked by irritability, poor sleep, hopelessness, and suicidality. He also suffered a traumatic brain injury in the military 25 years ago.

Police bring Mr. J to the ER after they find him wandering near traffic and speaking incoherently. His feet and hands jerk on the way to the hospital, leading police to suspect that Mr. J has suffered a grand mal seizure.

In the ER, Mr. J appears confused, has visual hallucinations, and moves his hands and feet involuntarily. His head and arms move erratically during the ER psychiatrist’s interview, and he says that his pelvis is arching forward and preventing him from walking steadily. The day before, he says, he saw frightening “visions” of a being who looked “like a photo negative.”

Mr. J has been seeing an outpatient psychiatrist, who has prescribed citalopram, 40 mg/d, for depression and clonazepam, 1 mg three times daily, for related anxiety symptoms.

The patient is disoriented and inattentive during the mental status examination. His cognitive deficits fluctuate in severity; at times he is aware of his surroundings, then suddenly loses this awareness.

Vital signs are stable. Physical exam shows Mr. J is approximately 30 lb underweight (97 lb) with a body mass index of 16.9 kg/m²—nearly 2 kg/m² below normal. He says he has been skipping meals because of poor appetite. He also has strikingly lizard-like, scaly skin.

Urine drug screen shows no signs of recent alcohol or substance abuse. Complete metabolic profile shows elevated liver enzymes, suggesting alcohol or illicit substance toxicity, medication toxicity, hepatitis, thyroid disorder, muscle disease, or a rare liver condition. EEG shows mild encephalopathy but no ictal activity.

poll here

The authors’ observations

Our psychiatric differential diagnosis is broad:

• visual and auditory hallucinations are concurrent in numerous disorders, including schizophrenia and depression
  
• visual hallucinations alone suggest dementia, delirium, or psychosis resulting from a medical condition, medication, or substance(s) of abuse¹
  
• Mr. J’s past head injury increases his risk of dementia and delirium
  
• his abrupt symptom onset and inattention suggest delirium.
  

Choreoathetosis can result from:

• medications such as stimulants and levodopa
  
• toxins
  
• systemic diseases such as systemic lupus erythematosus, thyrotoxicosis, or stroke
  
• degenerative brain diseases such as Huntington’s disease
  
• or focal brain diseases such as tumors.²
  

Although the test results narrow the differential diagnosis, we still have to consider numerous medical conditions that can cause delirium, such as trauma, cerebral vascular accident, intracerebral masses, CNS infection, and inflammatory disease.

poll here

History: collateral contributions

We refer Mr. J for lumbar puncture to rule out CNS infection and MRI to rule out tumor, abscess, or other structural brain abnormalities that could cause seizure. Results are unremarkable.

We then speak with Mr. J’s outpatient psychiatrist, who reports that Mr. J has had no residual cognitive impairment from his head injury. She adds, though, that he often develops cognitive problems after consuming large amounts of a traditional South Pacific beverage containing kava (Piper methysticum). She explains that Mr. J socializes with fellow Fijians who drink kava at gatherings, and that he often drinks kava to excess. She attributes his dry, scaly skin to excessive kava use.

Upon questioning, Mr. J says he consumes about a half-pound of kava root per day. He says he uses the root to make a tea-like beverage that, like alcohol, induces euphoria and relaxation. He says he began doing this in his youth back in Fiji, and now drinks “many cups” of kava per day.

Mr. J states that his current episode of strange movements and visual hallucinations began hours after he drank several cups of kava the day before police brought him to the ER. He considers his new psychiatric symptoms Jesus’ punishment for drinking kava.

The authors’ observations

Mr. J’s persecutory delusions suggest that he does not fully associate his symptoms with excessive kava use, but his abnormal movements, weight loss, skin changes, liver function abnormalities, and mental status changes are known adverse effects of kava.³ We diagnose substance-induced delirium rather than substance intoxication or substance-induced psychosis because:

• Mr. J’s cognitive symptoms are more severe than those caused by kava intoxication
  
• his psychotic symptoms occur only when he is delirious
  
• his disturbed consciousness, cognitive, and perceptual disturbances and the temporal relationship between symptom onset and massive kava use match DSM-IV-TR criteria for substance-induced delirium.⁴
  

Being aware of cultural customs and beliefs in your practice area can alert you to herbal substance use in various populations, such as kava by patients from the South Pacific or echinacea, goldenseal, and burdock by some Native Americans (see Related resources).

Medicinal use. Patients often use kava and other herbal supplements—including fatty acids, ginkgo biloba, ginseng, St. John’s wort, valerian, and others—with or instead of prescription drugs to alleviate psychiatric symptoms. Complementary and alternative medicine practitioners use kava to treat anxiety, for example (Box).

Anxiety and depression are among the most common reasons persons seek complementary or alternative treatment. In a national survey, 57% of respondents who suffered “anxiety attacks” and 54% of those with “severe depression” reported using such therapies.⁸ Nearly 1 in 5 persons who take prescription drugs also take herbs and/or high-dose vitamin supplements.⁹

Herbal products have been shown to cause adverse effects (Table 1).¹⁰ Kava, for example, has been associated with hepatotoxicity, dermopathy, movement disorders, GI disturbance, and weight loss. Standardized extracts such as capsules and tinctures appear more likely to cause adverse effects than traditional extractions, such as a beverage made by infusing kava root.⁵

Kava toxicity has been reported among heavy users. Although the dosage at which kava becomes dangerous is unknown, the FDA recommends that users not exceed typical dosages (50 to 280 mg/d) and use kava only under a physician’s supervision.¹¹

Also, interactions between herbal products and allopathic medications can cause substantial morbidity (Table 2). St. John’s wort, for example, can lead to serotonin syndrome when combined with selective serotonin reuptake inhibitors (SSRIs)¹² and can reduce blood levels of psychotropics metabolized by the cytochrome P-450 3A4 isoenzyme, such as alprazolam and carbamazepine.

Mr. J combined kava with clonazepam. Both substances affect gamma-aminobutyric (GABA) receptors, increasing the risk of sedation by depressing the CNS.

Table 1

Possible adverse effects of herbal supplements
used for psychiatric symptoms

Potential adverse interactions between psychotropics and complementary/alternative medications

Ask about alternative medicine use

According to a national survey,¹³ many patients do not tell allopathic physicians they are using complementary or alternative medications because:

• “It wasn’t important for the doctor to know.”
  
• “The doctor never asked.”
  
• “It was none of the doctor’s business.”
  
• “The doctor would not understand.”
  
• or “The doctor would disapprove or discourage CAM use.”
  

• routinely question patients about use of alternative therapies
  
• discuss safety and efficacy of commonly used alternative treatments
  
• discuss merits of alternative treatments
  
• provide information on the effectiveness and risks of various treatments
  
• learn about alternative therapies by consulting the Physicians’ Desk Reference (PDR) for Herbal Medicines or similar references
  
• help patients make decisions about alternative treatments, such as finding a qualified, licensed alternative provider.
  

Treatment: quick resolution

We admit Mr. J to the inpatient psychiatry unit. There, we continue his outpatient prescription medications at the same dosages and block access to nonprescription substances. His symptoms begin to improve during the first day of hospitalization. His choreoathetosis, hallucinations, and confusion resolve within 48 hours, and he is medically stable.

We discharge Mr. J after 2 days and continue citalopram and clonazepam at the same dosages.

The authors’ observations

Kava reaches peak plasma levels 1.8 hours after oral dosing and has a short (9-hour) elimination half-life. As a result, kava intoxication symptoms tend to resolve rapidly, as in Mr. J’s case.

Although Mr. J is medically stable, liver damage associated with kava use can be irreversible, prompting some European countries to ban its sale. Make sure patients who report kava use are aware of its hepatotoxicity risk.

Follow-up: kicking the kava habit

Two weeks after Mr. J’s discharge, his psychiatrist notes that his mental status has returned to baseline and that his skin has improved dramatically. The patient is following his citalopram and clonazepam regimen, and he seems more aware of kava’s potential adverse effects.

Mr. J reports that he has not consumed kava since his hospitalization. He has been eating four meals per day and has gained 9 lb. He is pleased with his improved appetite and is motivated to continue abstaining from kava.

Related resources

• National Center for Complementary and Alternative Medicine. http://nccam.nih.gov.
  
• Physicians Desk Reference (PDR) for herbal medicines, 3rd ed. Montvale, NJ: Thomson PDR; 2004.
  
• Ernst E, Pittler MH, Stevinson C, et al. The desktop guide to complementary and alternative medicine. Edinburgh, UK: Mosby; 2001.
  

• Alprazolam • Xanax
  
• Buspirone • BuSpar
  
• Carbamazepine • Equetro, others
  
• Carbidopa • Lodosyn
  
• Citalopram • Celexa
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Trazodone • Desyrel
  

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

History: a ‘negative’ view

Mr. J, a 50-year-old native of Fiji, has had depression and substance abuse disorder for more than 10 years, marked by irritability, poor sleep, hopelessness, and suicidality. He also suffered a traumatic brain injury in the military 25 years ago.

Police bring Mr. J to the ER after they find him wandering near traffic and speaking incoherently. His feet and hands jerk on the way to the hospital, leading police to suspect that Mr. J has suffered a grand mal seizure.

In the ER, Mr. J appears confused, has visual hallucinations, and moves his hands and feet involuntarily. His head and arms move erratically during the ER psychiatrist’s interview, and he says that his pelvis is arching forward and preventing him from walking steadily. The day before, he says, he saw frightening “visions” of a being who looked “like a photo negative.”

Mr. J has been seeing an outpatient psychiatrist, who has prescribed citalopram, 40 mg/d, for depression and clonazepam, 1 mg three times daily, for related anxiety symptoms.

The patient is disoriented and inattentive during the mental status examination. His cognitive deficits fluctuate in severity; at times he is aware of his surroundings, then suddenly loses this awareness.

Vital signs are stable. Physical exam shows Mr. J is approximately 30 lb underweight (97 lb) with a body mass index of 16.9 kg/m²—nearly 2 kg/m² below normal. He says he has been skipping meals because of poor appetite. He also has strikingly lizard-like, scaly skin.

Urine drug screen shows no signs of recent alcohol or substance abuse. Complete metabolic profile shows elevated liver enzymes, suggesting alcohol or illicit substance toxicity, medication toxicity, hepatitis, thyroid disorder, muscle disease, or a rare liver condition. EEG shows mild encephalopathy but no ictal activity.

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The authors’ observations

Our psychiatric differential diagnosis is broad:

• visual and auditory hallucinations are concurrent in numerous disorders, including schizophrenia and depression
  
• visual hallucinations alone suggest dementia, delirium, or psychosis resulting from a medical condition, medication, or substance(s) of abuse¹
  
• Mr. J’s past head injury increases his risk of dementia and delirium
  
• his abrupt symptom onset and inattention suggest delirium.
  

Choreoathetosis can result from:

• medications such as stimulants and levodopa
  
• toxins
  
• systemic diseases such as systemic lupus erythematosus, thyrotoxicosis, or stroke
  
• degenerative brain diseases such as Huntington’s disease
  
• or focal brain diseases such as tumors.²
  

Although the test results narrow the differential diagnosis, we still have to consider numerous medical conditions that can cause delirium, such as trauma, cerebral vascular accident, intracerebral masses, CNS infection, and inflammatory disease.

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History: collateral contributions

We refer Mr. J for lumbar puncture to rule out CNS infection and MRI to rule out tumor, abscess, or other structural brain abnormalities that could cause seizure. Results are unremarkable.

We then speak with Mr. J’s outpatient psychiatrist, who reports that Mr. J has had no residual cognitive impairment from his head injury. She adds, though, that he often develops cognitive problems after consuming large amounts of a traditional South Pacific beverage containing kava (Piper methysticum). She explains that Mr. J socializes with fellow Fijians who drink kava at gatherings, and that he often drinks kava to excess. She attributes his dry, scaly skin to excessive kava use.

Upon questioning, Mr. J says he consumes about a half-pound of kava root per day. He says he uses the root to make a tea-like beverage that, like alcohol, induces euphoria and relaxation. He says he began doing this in his youth back in Fiji, and now drinks “many cups” of kava per day.

Mr. J states that his current episode of strange movements and visual hallucinations began hours after he drank several cups of kava the day before police brought him to the ER. He considers his new psychiatric symptoms Jesus’ punishment for drinking kava.

The authors’ observations

Mr. J’s persecutory delusions suggest that he does not fully associate his symptoms with excessive kava use, but his abnormal movements, weight loss, skin changes, liver function abnormalities, and mental status changes are known adverse effects of kava.³ We diagnose substance-induced delirium rather than substance intoxication or substance-induced psychosis because:

• Mr. J’s cognitive symptoms are more severe than those caused by kava intoxication
  
• his psychotic symptoms occur only when he is delirious
  
• his disturbed consciousness, cognitive, and perceptual disturbances and the temporal relationship between symptom onset and massive kava use match DSM-IV-TR criteria for substance-induced delirium.⁴
  

Being aware of cultural customs and beliefs in your practice area can alert you to herbal substance use in various populations, such as kava by patients from the South Pacific or echinacea, goldenseal, and burdock by some Native Americans (see Related resources).

Medicinal use. Patients often use kava and other herbal supplements—including fatty acids, ginkgo biloba, ginseng, St. John’s wort, valerian, and others—with or instead of prescription drugs to alleviate psychiatric symptoms. Complementary and alternative medicine practitioners use kava to treat anxiety, for example (Box).

Anxiety and depression are among the most common reasons persons seek complementary or alternative treatment. In a national survey, 57% of respondents who suffered “anxiety attacks” and 54% of those with “severe depression” reported using such therapies.⁸ Nearly 1 in 5 persons who take prescription drugs also take herbs and/or high-dose vitamin supplements.⁹

Herbal products have been shown to cause adverse effects (Table 1).¹⁰ Kava, for example, has been associated with hepatotoxicity, dermopathy, movement disorders, GI disturbance, and weight loss. Standardized extracts such as capsules and tinctures appear more likely to cause adverse effects than traditional extractions, such as a beverage made by infusing kava root.⁵

Kava toxicity has been reported among heavy users. Although the dosage at which kava becomes dangerous is unknown, the FDA recommends that users not exceed typical dosages (50 to 280 mg/d) and use kava only under a physician’s supervision.¹¹

Also, interactions between herbal products and allopathic medications can cause substantial morbidity (Table 2). St. John’s wort, for example, can lead to serotonin syndrome when combined with selective serotonin reuptake inhibitors (SSRIs)¹² and can reduce blood levels of psychotropics metabolized by the cytochrome P-450 3A4 isoenzyme, such as alprazolam and carbamazepine.

Mr. J combined kava with clonazepam. Both substances affect gamma-aminobutyric (GABA) receptors, increasing the risk of sedation by depressing the CNS.

Table 1

Possible adverse effects of herbal supplements
used for psychiatric symptoms

Potential adverse interactions between psychotropics and complementary/alternative medications

Ask about alternative medicine use

According to a national survey,¹³ many patients do not tell allopathic physicians they are using complementary or alternative medications because:

• “It wasn’t important for the doctor to know.”
  
• “The doctor never asked.”
  
• “It was none of the doctor’s business.”
  
• “The doctor would not understand.”
  
• or “The doctor would disapprove or discourage CAM use.”
  

• routinely question patients about use of alternative therapies
  
• discuss safety and efficacy of commonly used alternative treatments
  
• discuss merits of alternative treatments
  
• provide information on the effectiveness and risks of various treatments
  
• learn about alternative therapies by consulting the Physicians’ Desk Reference (PDR) for Herbal Medicines or similar references
  
• help patients make decisions about alternative treatments, such as finding a qualified, licensed alternative provider.
  

Treatment: quick resolution

We admit Mr. J to the inpatient psychiatry unit. There, we continue his outpatient prescription medications at the same dosages and block access to nonprescription substances. His symptoms begin to improve during the first day of hospitalization. His choreoathetosis, hallucinations, and confusion resolve within 48 hours, and he is medically stable.

We discharge Mr. J after 2 days and continue citalopram and clonazepam at the same dosages.

The authors’ observations

Kava reaches peak plasma levels 1.8 hours after oral dosing and has a short (9-hour) elimination half-life. As a result, kava intoxication symptoms tend to resolve rapidly, as in Mr. J’s case.

Although Mr. J is medically stable, liver damage associated with kava use can be irreversible, prompting some European countries to ban its sale. Make sure patients who report kava use are aware of its hepatotoxicity risk.

Follow-up: kicking the kava habit

Two weeks after Mr. J’s discharge, his psychiatrist notes that his mental status has returned to baseline and that his skin has improved dramatically. The patient is following his citalopram and clonazepam regimen, and he seems more aware of kava’s potential adverse effects.

Mr. J reports that he has not consumed kava since his hospitalization. He has been eating four meals per day and has gained 9 lb. He is pleased with his improved appetite and is motivated to continue abstaining from kava.

Related resources

• National Center for Complementary and Alternative Medicine. http://nccam.nih.gov.
  
• Physicians Desk Reference (PDR) for herbal medicines, 3rd ed. Montvale, NJ: Thomson PDR; 2004.
  
• Ernst E, Pittler MH, Stevinson C, et al. The desktop guide to complementary and alternative medicine. Edinburgh, UK: Mosby; 2001.
  

• Alprazolam • Xanax
  
• Buspirone • BuSpar
  
• Carbamazepine • Equetro, others
  
• Carbidopa • Lodosyn
  
• Citalopram • Celexa
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Trazodone • Desyrel
  

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

Hypothyroidism—even when occult or subclinical—can cause subtle or frank changes in energy, mood, anxiety level, or cognition. Some patients’ affective symptoms remit with thyroid hormone replacement or with antidepressants only after a euthyroid state is established.

To help you recognize hypothyroidism in patients presenting with psychiatric illnesses and provide effective treatment, this article describes:

• hypothyroidism’s signs and symptoms
• primary and subclinical hypothyroidism, thyroiditis, central hypothyroidism, and thyroid hormone resistance
• laboratory screening for thyroid dysfunction in patients with psychiatric symptoms.

Overlapping clinical signs

Thyroid hormone is required for the metabolic activity of every cell in the body. When patients experience symptoms related to abnormal functioning of the hypothalamic-pituitary-thyroid axis (Figure), psychiatrists often are the first professionals they consult.

Diagnosis of thyroid disorders is based on biochemical and clinical data (Box 1),¹ which might not be congruent. Clinical symptoms of hypothyroidism, for example, are notoriously variable. Severe biochemical hypothyroidism may be associated with mild clinical symptoms, whereas mild biochemical hypothyroidism may be associated with severe symptoms.²

Patients with thyroid disturbance and psychiatric symptoms most often are diagnosed with a depressive-spectrum syndrome. Most common are:

• atypical depression (which may present as dysthymia)
• bipolar spectrum syndrome (including manic-depression, mixed mania, bipolar depression, rapid-cycling bipolar disorder, cyclothymia, and premenstrual syndromes)
• borderline personality disorder
• or psychotic disorder (typically paranoid psychosis).

Psychiatric symptoms of hypothyroidism (Table 1) are often prominent or even primary. Patients commonly show:

• impaired attention, concentration, learning, and memory
• psychomotor slowing
• and/or mental dullness.

Table 1

Hypothyroidism’s psychiatric signs and symptoms

Box 1

Figure Thyroid hormone regulation: The hypothalamic-pituitary-thyroid axis

Thyroid-stimulating hormone (TSH, thyrotropin) released into circulation by the pituitary stimulates the thyroid to synthesize and release thyroid hormone, including triiodothyronine (T3) and thyroxine (T4). TSH is regulated by hypothalamic elaboration of thyrotropin-releasing hormone (TRH), which stimulates TSH release in a dose-dependent manner. Negative feedback from T3 and T4 downregulates TRH gene expression and restrains the pituitary from responding to TSH. Most T3—the active hormone—is formed in circulation or in target tissues by deiodination of T4 by selenium-containing enzymes.

Illustration for Current Psychiatry by Rich LaroccoThe degree of impairment may depend on the patient’s normal functional level. For example, a well-educated patient of mine with thyroiditis-related hypothyroidism reported word-finding difficulties. Instead of asking her husband to take a bottle of wine from the rack, she asked him to take a bottle of wine from the “thing.”

Loss of vitality, fatigue, lethargy, hypersomnia (especially if sleep apnea is present), and depressed mood also are commonly seen.

Depressive symptoms. Hypothyroid patients usually meet several criteria for a major depressive episode—such as concentration difficulties, lassitude, low libido, and sometimes pessimism or sadness—and symptoms improve after sustained thyroid hormone replacement therapy.³ Women with mild hypothyroidism who screen negative for a psychiatric syndrome show statistically significant mood improvement and improved verbal fluency after 6 months of levothyroxine replacement therapy.⁴

In some patients with no clear evidence of a biochemical or clinical thyroid disorder, mood symptoms nevertheless respond to thyroid hormone augmentation of antidepressants.⁵

Anxiety symptoms. Occasionally thyroid dysfunction is seen in patients with anxiety disorders, including panic disorder, agoraphobia, social phobia, performance anxiety, post-traumatic stress disorder, and generalized anxiety disorder.⁶

It may seem counterintuitive, but hypothyroidism is probably as common as hyperthyroidism in extremely anxious patients. Both hypoand hyperthyroidism are seen much more often in patients with panic-level anxiety than in the general population.

In a sample of 144 consecutive female psychiatric patients with a lifetime history of panic disorder and/or agoraphobia:

• 27% had a history of thyroid disorder
• 17% had hypothyroidism
• 8% had hyperthyroidism.⁷

Hypothyroid symptoms. Associated symptoms of hypothyroidism (Table 2) may include cold intolerance, lack of or reduced perspiration, dry skin, constipation, lethargy, psychomotor slowness, and subjective paresthesias and muscle pains. Edema is often present. The face typically is swollen or “puffy” in the morning, but by evening the lower legs (and not the face) are edematous.

Deep tendon reflexes usually relax slowly after initial stimulation. Vascular resistance is increased, but hypertension is not usual. Noradrenergic systems become more active in a compensatory, counter-regulatory manner; however, bradycardia—when present—is sometimes profound. Weight gain can occur but often is conspicuously absent.

Severe hypothyroidism presents with paradoxical tremendous agitation, paranoia, and aggressiveness. The skin is leathery, and facies are characteristically rough. Myxedema is fairly common, even in high-functioning patients. I have seen only one case of so-called “myxedema madness;” the female patient’s hyperarousal, yelling, cursing, grossly poor cognitive ability, and loosely conceived paranoid delusions are unforgettable.

Galactorrhea (related to hyperprolactinemia) can be a symptom of severe hypothyroidism, presumably from increased hypothalamic thyrotropin-releasing hormone (TRH) drive. TRH is the main known secretagogue for pituitary prolactin secretion. Infertility, oligomenorrhea, or amenorrhea could be part of the hypothyroid clinical picture.

Other symptoms. Macroglossia and hypertrophy of the uvula are possible; in a recent report, dysarthria resulting from these oral changes was the only presenting symptom of a hypothyroid man.⁸ Dysarthria promptly corrected after levothyroxine replacement.

Hypothyroidism is a primary cause of central sleep apnea caused by dysfunction of ventilatory control and/or reduction in airway aperture.

Table 2

Hypothyroidism’s other signs and symptoms

Causes of thyroid disorders

Primary hypothyroidism results from thyroid gland failure. The many causes include iodine deficiency, but most cases of adult-onset or acquired hypothyroidism are attributed to autoimmune thyroiditis. In primary hypothyroidism, low serum T4 and/or T3 are seen in combination with elevated serum TSH. Circulating free T4 diminishes sooner than free T3 does as the body attempts to preserve active hormone levels. In turn, total T4 and T3 diminish sooner than free hormone concentrations. A compensatory increase in pituitary-elaborated TSH is seen as the brain and pituitary attempt to stimulate the thyroid to produce adequate thyroid hormone.

In subclinical hypothyroidism, circulating free thyroid hormone concentrations are within the normal laboratory range (typically in the lower range), but TSH is elevated. TSH concentrations >3.0 mIU/mL call for repeat or follow-up biochemistry and clinical correlation.

The decision to treat subclinical hypothyroidism with thyroid hormone replacement is less controversial in psychiatry than in endocrinology. Psychiatric patients with subclinical hypothyroidism—especially those with incomplete responses to psychotropic therapy—should usually be treated with thyroid hormone (Box 2).¹

Free T3 levels in the lower 20% of the laboratory’s normal range are cause for pause in a patient with a mood or psychotic disorder and any of hypothyroidism’s clinical stigmata, even if thyroxine and TSH concentrations are normal.

Thyroiditis is characterized by thyroid gland inflammation. The thyroid may be painful or nonpainful, enlarged, fleshy, goitrous, normal in size, or atrophic and fibrotic (especially late in the course).

Postulated precipitants include viruses and other infectious agents, vaccines, iodine excess, lithium therapy (Box 3),⁹ tobacco smoke, environmental chemicals or toxins, irradiation, and—arguably—cortically-mediated (psychological) stress in vulnerable individuals.

Clinically, thyroiditis syndromes often have a long prodromal phase, wax and wane in severity, have an insidious and sometimes silent course, and can be serially associated with hyperthyroidism (especially early in the course), euthyroidism, or hypothyroidism (especially late in the course). Most thyroiditis syndromes appear to resolve spontaneously, but many become chronic or show evidence of subtle thyroid dysfunction years after the first occurrence or diagnosis.

Most presentations are nonspecific; symptoms may be limited to lethargy, fatigue, and depression. Increased antithyroid antibody titers have been linked with psychotic and depressive syndromes in borderline personality disorder.¹⁰

In early thyroiditis, thyroxine and triiodothyronine secretion is often elevated, with low or suppressed TSH. However, antithyroid antibody production is associated with a significantly increased risk of eventual subclinical or frank hypothyroidism. Permanent hypothyroidism develops eventually in at least one-half of women with histories of postpartum thyroiditis.¹¹

Central hypothyroidism stems from TSH deficiency. Both pituitary thyrotrophic failure and hypothalamic failure—secondary and tertiary hypothyroidism, respectively—are considered central (or “secondary”). Hypothyroidism of pituitary and hypothalamic origins are lumped together as “central” because it is often very difficult to differentiate these pathologies.

Thyroid hormone resistance, in which end-organ or cellular resistance to thyroid hormone signals is seen, is an increasingly recognized syndrome in clinical medicine. The typical case is an euthyroid or hypothyroid individual with elevated T4 and T3 and nonsuppressed or even frankly elevated TSH. Inappropriately elevated TSH combined with high thyroid hormone levels also can be seen in TSH-secreting pituitary tumors, although the clinical picture in this case is one of hyperthyroidism.

Thyroid hormone resistance ranges from euthyroid and clinically transparent to profoundly hypothyroid, and different organs in the same patient may show different sensitivities to thyroid hormone. Clinical features vary, depending on the strength of thyroid hormone resistance.

Early emergence of resistance (as would be expected in someone with an inherited thyroid hormone receptor abnormality) leads to developmental problems, including:

• short stature
• mental or learning disabilities (including attention deficits).

In a study of 18 families with strong history of generalized resistance to thyroid hormone, 70% of affected children met diagnostic criteria for attention-deficit/hyperactivity disorder.¹²

Box 2

Box 3

Laboratory screening

TSH and thyroid hormones. The basic thyroid screen is a combination of serum levels of TSH (“sensitive TSH”) and free thyroid hormones.

TSH has a circadian rhythm, with a nocturnal surge amounting to a 50% to 200% increase over daytime levels, beginning at around 6 to 8 PM. Peak TSH pulsatile activity and levels are seen after sleep begins—usually after midnight—with trough levels and fewest TSH pulses in late morning and early afternoon.^13,14 This rhythm implies that the most accurate TSH measurement may be obtained by drawing blood in the morning before 9 AM. I have seen subclinical hypothyroidism missed when clinicians relied on afternoon TSH levels.

In general medicine, TSH alone frequently is used as a routine screening tool. In psychiatric practice, however, I recommend supplementing TSH with free T3 and free T4 because thyroid system dysfunction is frequent in psychiatric syndromes. If laboratory costs are a concern, free T4 with TSH usually suffices for initial screening.

Although the unbound, free fractions of T3 and T4 are of primary interest, total T4 and total T3 are necessary to assess the thyroid gland’s synthetic capacity. When clinical evidence suggests abnormal thyroid hormone function, order repeated or serial biochemical testing. Marginal biochemical results also mandate repeat thyroid function studies, expanded to include:

• total thyroid hormone concentrations (ideally T4 and T3)
• antithyroid antibodies
• serum cholesterol
• prolactin.

Antithyroid antibodies. Obtain antithyroglobulin and antithyroid microsomal antibody titers if:

• thyroid hormone indices are abnormal or marginal—in either direction
• or the patient now has, has had, or has a family history of autoimmune-mediated symptoms, such as lupus erythematosus or rheumatoid arthritis.

Negative or low antithyroid autoantibody titers do not rule out thyroiditis as a cause of hypothyroidism, as these titers are most likely to be generated during periods of active inflammation.

Many autoantibodies react with thyroid-related elements. Most clinical laboratories can quantify antibodies directed against thyroid peroxidase—also called antimicrosomal antibodies—and thyroglobulin. The presence of these antibodies is associated with thyroid inflammation and a risk of progression to thyroid failure and hypothyroidism.

Other laboratory findings of hypothyroidism include hypercholesterolemia, mild hyperprolactinemia, and types of anemia (including iron-deficiency anemia with low ferritin levels).

Related resources

• American Thyroid Association. www.thyroid.org.
• Dunn JT. Guarding our nation’s thyroid health. J Clin Endocrinol Metab 2001;872:486-8.
• Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-55.
• Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biol Psychiatry 2006;60(5):500-6.

Hypothyroidism—even when occult or subclinical—can cause subtle or frank changes in energy, mood, anxiety level, or cognition. Some patients’ affective symptoms remit with thyroid hormone replacement or with antidepressants only after a euthyroid state is established.

To help you recognize hypothyroidism in patients presenting with psychiatric illnesses and provide effective treatment, this article describes:

• hypothyroidism’s signs and symptoms
• primary and subclinical hypothyroidism, thyroiditis, central hypothyroidism, and thyroid hormone resistance
• laboratory screening for thyroid dysfunction in patients with psychiatric symptoms.

Overlapping clinical signs

Thyroid hormone is required for the metabolic activity of every cell in the body. When patients experience symptoms related to abnormal functioning of the hypothalamic-pituitary-thyroid axis (Figure), psychiatrists often are the first professionals they consult.

Diagnosis of thyroid disorders is based on biochemical and clinical data (Box 1),¹ which might not be congruent. Clinical symptoms of hypothyroidism, for example, are notoriously variable. Severe biochemical hypothyroidism may be associated with mild clinical symptoms, whereas mild biochemical hypothyroidism may be associated with severe symptoms.²

Patients with thyroid disturbance and psychiatric symptoms most often are diagnosed with a depressive-spectrum syndrome. Most common are:

• atypical depression (which may present as dysthymia)
• bipolar spectrum syndrome (including manic-depression, mixed mania, bipolar depression, rapid-cycling bipolar disorder, cyclothymia, and premenstrual syndromes)
• borderline personality disorder
• or psychotic disorder (typically paranoid psychosis).

Psychiatric symptoms of hypothyroidism (Table 1) are often prominent or even primary. Patients commonly show:

• impaired attention, concentration, learning, and memory
• psychomotor slowing
• and/or mental dullness.

Table 1

Hypothyroidism’s psychiatric signs and symptoms

Box 1

Figure Thyroid hormone regulation: The hypothalamic-pituitary-thyroid axis

Thyroid-stimulating hormone (TSH, thyrotropin) released into circulation by the pituitary stimulates the thyroid to synthesize and release thyroid hormone, including triiodothyronine (T3) and thyroxine (T4). TSH is regulated by hypothalamic elaboration of thyrotropin-releasing hormone (TRH), which stimulates TSH release in a dose-dependent manner. Negative feedback from T3 and T4 downregulates TRH gene expression and restrains the pituitary from responding to TSH. Most T3—the active hormone—is formed in circulation or in target tissues by deiodination of T4 by selenium-containing enzymes.

Illustration for Current Psychiatry by Rich LaroccoThe degree of impairment may depend on the patient’s normal functional level. For example, a well-educated patient of mine with thyroiditis-related hypothyroidism reported word-finding difficulties. Instead of asking her husband to take a bottle of wine from the rack, she asked him to take a bottle of wine from the “thing.”

Loss of vitality, fatigue, lethargy, hypersomnia (especially if sleep apnea is present), and depressed mood also are commonly seen.

Depressive symptoms. Hypothyroid patients usually meet several criteria for a major depressive episode—such as concentration difficulties, lassitude, low libido, and sometimes pessimism or sadness—and symptoms improve after sustained thyroid hormone replacement therapy.³ Women with mild hypothyroidism who screen negative for a psychiatric syndrome show statistically significant mood improvement and improved verbal fluency after 6 months of levothyroxine replacement therapy.⁴

In some patients with no clear evidence of a biochemical or clinical thyroid disorder, mood symptoms nevertheless respond to thyroid hormone augmentation of antidepressants.⁵

Anxiety symptoms. Occasionally thyroid dysfunction is seen in patients with anxiety disorders, including panic disorder, agoraphobia, social phobia, performance anxiety, post-traumatic stress disorder, and generalized anxiety disorder.⁶

It may seem counterintuitive, but hypothyroidism is probably as common as hyperthyroidism in extremely anxious patients. Both hypoand hyperthyroidism are seen much more often in patients with panic-level anxiety than in the general population.

In a sample of 144 consecutive female psychiatric patients with a lifetime history of panic disorder and/or agoraphobia:

• 27% had a history of thyroid disorder
• 17% had hypothyroidism
• 8% had hyperthyroidism.⁷

Hypothyroid symptoms. Associated symptoms of hypothyroidism (Table 2) may include cold intolerance, lack of or reduced perspiration, dry skin, constipation, lethargy, psychomotor slowness, and subjective paresthesias and muscle pains. Edema is often present. The face typically is swollen or “puffy” in the morning, but by evening the lower legs (and not the face) are edematous.

Deep tendon reflexes usually relax slowly after initial stimulation. Vascular resistance is increased, but hypertension is not usual. Noradrenergic systems become more active in a compensatory, counter-regulatory manner; however, bradycardia—when present—is sometimes profound. Weight gain can occur but often is conspicuously absent.

Severe hypothyroidism presents with paradoxical tremendous agitation, paranoia, and aggressiveness. The skin is leathery, and facies are characteristically rough. Myxedema is fairly common, even in high-functioning patients. I have seen only one case of so-called “myxedema madness;” the female patient’s hyperarousal, yelling, cursing, grossly poor cognitive ability, and loosely conceived paranoid delusions are unforgettable.

Galactorrhea (related to hyperprolactinemia) can be a symptom of severe hypothyroidism, presumably from increased hypothalamic thyrotropin-releasing hormone (TRH) drive. TRH is the main known secretagogue for pituitary prolactin secretion. Infertility, oligomenorrhea, or amenorrhea could be part of the hypothyroid clinical picture.

Other symptoms. Macroglossia and hypertrophy of the uvula are possible; in a recent report, dysarthria resulting from these oral changes was the only presenting symptom of a hypothyroid man.⁸ Dysarthria promptly corrected after levothyroxine replacement.

Hypothyroidism is a primary cause of central sleep apnea caused by dysfunction of ventilatory control and/or reduction in airway aperture.

Table 2

Hypothyroidism’s other signs and symptoms

Causes of thyroid disorders

Primary hypothyroidism results from thyroid gland failure. The many causes include iodine deficiency, but most cases of adult-onset or acquired hypothyroidism are attributed to autoimmune thyroiditis. In primary hypothyroidism, low serum T4 and/or T3 are seen in combination with elevated serum TSH. Circulating free T4 diminishes sooner than free T3 does as the body attempts to preserve active hormone levels. In turn, total T4 and T3 diminish sooner than free hormone concentrations. A compensatory increase in pituitary-elaborated TSH is seen as the brain and pituitary attempt to stimulate the thyroid to produce adequate thyroid hormone.

In subclinical hypothyroidism, circulating free thyroid hormone concentrations are within the normal laboratory range (typically in the lower range), but TSH is elevated. TSH concentrations >3.0 mIU/mL call for repeat or follow-up biochemistry and clinical correlation.

The decision to treat subclinical hypothyroidism with thyroid hormone replacement is less controversial in psychiatry than in endocrinology. Psychiatric patients with subclinical hypothyroidism—especially those with incomplete responses to psychotropic therapy—should usually be treated with thyroid hormone (Box 2).¹

Free T3 levels in the lower 20% of the laboratory’s normal range are cause for pause in a patient with a mood or psychotic disorder and any of hypothyroidism’s clinical stigmata, even if thyroxine and TSH concentrations are normal.

Thyroiditis is characterized by thyroid gland inflammation. The thyroid may be painful or nonpainful, enlarged, fleshy, goitrous, normal in size, or atrophic and fibrotic (especially late in the course).

Postulated precipitants include viruses and other infectious agents, vaccines, iodine excess, lithium therapy (Box 3),⁹ tobacco smoke, environmental chemicals or toxins, irradiation, and—arguably—cortically-mediated (psychological) stress in vulnerable individuals.

Clinically, thyroiditis syndromes often have a long prodromal phase, wax and wane in severity, have an insidious and sometimes silent course, and can be serially associated with hyperthyroidism (especially early in the course), euthyroidism, or hypothyroidism (especially late in the course). Most thyroiditis syndromes appear to resolve spontaneously, but many become chronic or show evidence of subtle thyroid dysfunction years after the first occurrence or diagnosis.

Most presentations are nonspecific; symptoms may be limited to lethargy, fatigue, and depression. Increased antithyroid antibody titers have been linked with psychotic and depressive syndromes in borderline personality disorder.¹⁰

In early thyroiditis, thyroxine and triiodothyronine secretion is often elevated, with low or suppressed TSH. However, antithyroid antibody production is associated with a significantly increased risk of eventual subclinical or frank hypothyroidism. Permanent hypothyroidism develops eventually in at least one-half of women with histories of postpartum thyroiditis.¹¹

Central hypothyroidism stems from TSH deficiency. Both pituitary thyrotrophic failure and hypothalamic failure—secondary and tertiary hypothyroidism, respectively—are considered central (or “secondary”). Hypothyroidism of pituitary and hypothalamic origins are lumped together as “central” because it is often very difficult to differentiate these pathologies.

Thyroid hormone resistance, in which end-organ or cellular resistance to thyroid hormone signals is seen, is an increasingly recognized syndrome in clinical medicine. The typical case is an euthyroid or hypothyroid individual with elevated T4 and T3 and nonsuppressed or even frankly elevated TSH. Inappropriately elevated TSH combined with high thyroid hormone levels also can be seen in TSH-secreting pituitary tumors, although the clinical picture in this case is one of hyperthyroidism.

Thyroid hormone resistance ranges from euthyroid and clinically transparent to profoundly hypothyroid, and different organs in the same patient may show different sensitivities to thyroid hormone. Clinical features vary, depending on the strength of thyroid hormone resistance.

Early emergence of resistance (as would be expected in someone with an inherited thyroid hormone receptor abnormality) leads to developmental problems, including:

• short stature
• mental or learning disabilities (including attention deficits).

In a study of 18 families with strong history of generalized resistance to thyroid hormone, 70% of affected children met diagnostic criteria for attention-deficit/hyperactivity disorder.¹²

Box 2

Box 3

Laboratory screening

TSH and thyroid hormones. The basic thyroid screen is a combination of serum levels of TSH (“sensitive TSH”) and free thyroid hormones.

TSH has a circadian rhythm, with a nocturnal surge amounting to a 50% to 200% increase over daytime levels, beginning at around 6 to 8 PM. Peak TSH pulsatile activity and levels are seen after sleep begins—usually after midnight—with trough levels and fewest TSH pulses in late morning and early afternoon.^13,14 This rhythm implies that the most accurate TSH measurement may be obtained by drawing blood in the morning before 9 AM. I have seen subclinical hypothyroidism missed when clinicians relied on afternoon TSH levels.

In general medicine, TSH alone frequently is used as a routine screening tool. In psychiatric practice, however, I recommend supplementing TSH with free T3 and free T4 because thyroid system dysfunction is frequent in psychiatric syndromes. If laboratory costs are a concern, free T4 with TSH usually suffices for initial screening.

Although the unbound, free fractions of T3 and T4 are of primary interest, total T4 and total T3 are necessary to assess the thyroid gland’s synthetic capacity. When clinical evidence suggests abnormal thyroid hormone function, order repeated or serial biochemical testing. Marginal biochemical results also mandate repeat thyroid function studies, expanded to include:

• total thyroid hormone concentrations (ideally T4 and T3)
• antithyroid antibodies
• serum cholesterol
• prolactin.

Antithyroid antibodies. Obtain antithyroglobulin and antithyroid microsomal antibody titers if:

• thyroid hormone indices are abnormal or marginal—in either direction
• or the patient now has, has had, or has a family history of autoimmune-mediated symptoms, such as lupus erythematosus or rheumatoid arthritis.

Negative or low antithyroid autoantibody titers do not rule out thyroiditis as a cause of hypothyroidism, as these titers are most likely to be generated during periods of active inflammation.

Many autoantibodies react with thyroid-related elements. Most clinical laboratories can quantify antibodies directed against thyroid peroxidase—also called antimicrosomal antibodies—and thyroglobulin. The presence of these antibodies is associated with thyroid inflammation and a risk of progression to thyroid failure and hypothyroidism.

Other laboratory findings of hypothyroidism include hypercholesterolemia, mild hyperprolactinemia, and types of anemia (including iron-deficiency anemia with low ferritin levels).

Related resources

• American Thyroid Association. www.thyroid.org.
• Dunn JT. Guarding our nation’s thyroid health. J Clin Endocrinol Metab 2001;872:486-8.
• Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-55.
• Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biol Psychiatry 2006;60(5):500-6.

Hypothyroidism—even when occult or subclinical—can cause subtle or frank changes in energy, mood, anxiety level, or cognition. Some patients’ affective symptoms remit with thyroid hormone replacement or with antidepressants only after a euthyroid state is established.

To help you recognize hypothyroidism in patients presenting with psychiatric illnesses and provide effective treatment, this article describes:

• hypothyroidism’s signs and symptoms
• primary and subclinical hypothyroidism, thyroiditis, central hypothyroidism, and thyroid hormone resistance
• laboratory screening for thyroid dysfunction in patients with psychiatric symptoms.

Overlapping clinical signs

Thyroid hormone is required for the metabolic activity of every cell in the body. When patients experience symptoms related to abnormal functioning of the hypothalamic-pituitary-thyroid axis (Figure), psychiatrists often are the first professionals they consult.

Diagnosis of thyroid disorders is based on biochemical and clinical data (Box 1),¹ which might not be congruent. Clinical symptoms of hypothyroidism, for example, are notoriously variable. Severe biochemical hypothyroidism may be associated with mild clinical symptoms, whereas mild biochemical hypothyroidism may be associated with severe symptoms.²

Patients with thyroid disturbance and psychiatric symptoms most often are diagnosed with a depressive-spectrum syndrome. Most common are:

• atypical depression (which may present as dysthymia)
• bipolar spectrum syndrome (including manic-depression, mixed mania, bipolar depression, rapid-cycling bipolar disorder, cyclothymia, and premenstrual syndromes)
• borderline personality disorder
• or psychotic disorder (typically paranoid psychosis).

Psychiatric symptoms of hypothyroidism (Table 1) are often prominent or even primary. Patients commonly show:

• impaired attention, concentration, learning, and memory
• psychomotor slowing
• and/or mental dullness.

Table 1

Hypothyroidism’s psychiatric signs and symptoms

Box 1

Figure Thyroid hormone regulation: The hypothalamic-pituitary-thyroid axis

Thyroid-stimulating hormone (TSH, thyrotropin) released into circulation by the pituitary stimulates the thyroid to synthesize and release thyroid hormone, including triiodothyronine (T3) and thyroxine (T4). TSH is regulated by hypothalamic elaboration of thyrotropin-releasing hormone (TRH), which stimulates TSH release in a dose-dependent manner. Negative feedback from T3 and T4 downregulates TRH gene expression and restrains the pituitary from responding to TSH. Most T3—the active hormone—is formed in circulation or in target tissues by deiodination of T4 by selenium-containing enzymes.

Illustration for Current Psychiatry by Rich LaroccoThe degree of impairment may depend on the patient’s normal functional level. For example, a well-educated patient of mine with thyroiditis-related hypothyroidism reported word-finding difficulties. Instead of asking her husband to take a bottle of wine from the rack, she asked him to take a bottle of wine from the “thing.”

Loss of vitality, fatigue, lethargy, hypersomnia (especially if sleep apnea is present), and depressed mood also are commonly seen.

Depressive symptoms. Hypothyroid patients usually meet several criteria for a major depressive episode—such as concentration difficulties, lassitude, low libido, and sometimes pessimism or sadness—and symptoms improve after sustained thyroid hormone replacement therapy.³ Women with mild hypothyroidism who screen negative for a psychiatric syndrome show statistically significant mood improvement and improved verbal fluency after 6 months of levothyroxine replacement therapy.⁴

In some patients with no clear evidence of a biochemical or clinical thyroid disorder, mood symptoms nevertheless respond to thyroid hormone augmentation of antidepressants.⁵

Anxiety symptoms. Occasionally thyroid dysfunction is seen in patients with anxiety disorders, including panic disorder, agoraphobia, social phobia, performance anxiety, post-traumatic stress disorder, and generalized anxiety disorder.⁶

It may seem counterintuitive, but hypothyroidism is probably as common as hyperthyroidism in extremely anxious patients. Both hypoand hyperthyroidism are seen much more often in patients with panic-level anxiety than in the general population.

In a sample of 144 consecutive female psychiatric patients with a lifetime history of panic disorder and/or agoraphobia:

• 27% had a history of thyroid disorder
• 17% had hypothyroidism
• 8% had hyperthyroidism.⁷

Hypothyroid symptoms. Associated symptoms of hypothyroidism (Table 2) may include cold intolerance, lack of or reduced perspiration, dry skin, constipation, lethargy, psychomotor slowness, and subjective paresthesias and muscle pains. Edema is often present. The face typically is swollen or “puffy” in the morning, but by evening the lower legs (and not the face) are edematous.

Deep tendon reflexes usually relax slowly after initial stimulation. Vascular resistance is increased, but hypertension is not usual. Noradrenergic systems become more active in a compensatory, counter-regulatory manner; however, bradycardia—when present—is sometimes profound. Weight gain can occur but often is conspicuously absent.

Severe hypothyroidism presents with paradoxical tremendous agitation, paranoia, and aggressiveness. The skin is leathery, and facies are characteristically rough. Myxedema is fairly common, even in high-functioning patients. I have seen only one case of so-called “myxedema madness;” the female patient’s hyperarousal, yelling, cursing, grossly poor cognitive ability, and loosely conceived paranoid delusions are unforgettable.

Galactorrhea (related to hyperprolactinemia) can be a symptom of severe hypothyroidism, presumably from increased hypothalamic thyrotropin-releasing hormone (TRH) drive. TRH is the main known secretagogue for pituitary prolactin secretion. Infertility, oligomenorrhea, or amenorrhea could be part of the hypothyroid clinical picture.

Other symptoms. Macroglossia and hypertrophy of the uvula are possible; in a recent report, dysarthria resulting from these oral changes was the only presenting symptom of a hypothyroid man.⁸ Dysarthria promptly corrected after levothyroxine replacement.

Hypothyroidism is a primary cause of central sleep apnea caused by dysfunction of ventilatory control and/or reduction in airway aperture.

Table 2

Hypothyroidism’s other signs and symptoms

Causes of thyroid disorders

Primary hypothyroidism results from thyroid gland failure. The many causes include iodine deficiency, but most cases of adult-onset or acquired hypothyroidism are attributed to autoimmune thyroiditis. In primary hypothyroidism, low serum T4 and/or T3 are seen in combination with elevated serum TSH. Circulating free T4 diminishes sooner than free T3 does as the body attempts to preserve active hormone levels. In turn, total T4 and T3 diminish sooner than free hormone concentrations. A compensatory increase in pituitary-elaborated TSH is seen as the brain and pituitary attempt to stimulate the thyroid to produce adequate thyroid hormone.

In subclinical hypothyroidism, circulating free thyroid hormone concentrations are within the normal laboratory range (typically in the lower range), but TSH is elevated. TSH concentrations >3.0 mIU/mL call for repeat or follow-up biochemistry and clinical correlation.

The decision to treat subclinical hypothyroidism with thyroid hormone replacement is less controversial in psychiatry than in endocrinology. Psychiatric patients with subclinical hypothyroidism—especially those with incomplete responses to psychotropic therapy—should usually be treated with thyroid hormone (Box 2).¹

Free T3 levels in the lower 20% of the laboratory’s normal range are cause for pause in a patient with a mood or psychotic disorder and any of hypothyroidism’s clinical stigmata, even if thyroxine and TSH concentrations are normal.

Thyroiditis is characterized by thyroid gland inflammation. The thyroid may be painful or nonpainful, enlarged, fleshy, goitrous, normal in size, or atrophic and fibrotic (especially late in the course).

Postulated precipitants include viruses and other infectious agents, vaccines, iodine excess, lithium therapy (Box 3),⁹ tobacco smoke, environmental chemicals or toxins, irradiation, and—arguably—cortically-mediated (psychological) stress in vulnerable individuals.

Clinically, thyroiditis syndromes often have a long prodromal phase, wax and wane in severity, have an insidious and sometimes silent course, and can be serially associated with hyperthyroidism (especially early in the course), euthyroidism, or hypothyroidism (especially late in the course). Most thyroiditis syndromes appear to resolve spontaneously, but many become chronic or show evidence of subtle thyroid dysfunction years after the first occurrence or diagnosis.

Most presentations are nonspecific; symptoms may be limited to lethargy, fatigue, and depression. Increased antithyroid antibody titers have been linked with psychotic and depressive syndromes in borderline personality disorder.¹⁰

In early thyroiditis, thyroxine and triiodothyronine secretion is often elevated, with low or suppressed TSH. However, antithyroid antibody production is associated with a significantly increased risk of eventual subclinical or frank hypothyroidism. Permanent hypothyroidism develops eventually in at least one-half of women with histories of postpartum thyroiditis.¹¹

Central hypothyroidism stems from TSH deficiency. Both pituitary thyrotrophic failure and hypothalamic failure—secondary and tertiary hypothyroidism, respectively—are considered central (or “secondary”). Hypothyroidism of pituitary and hypothalamic origins are lumped together as “central” because it is often very difficult to differentiate these pathologies.

Thyroid hormone resistance, in which end-organ or cellular resistance to thyroid hormone signals is seen, is an increasingly recognized syndrome in clinical medicine. The typical case is an euthyroid or hypothyroid individual with elevated T4 and T3 and nonsuppressed or even frankly elevated TSH. Inappropriately elevated TSH combined with high thyroid hormone levels also can be seen in TSH-secreting pituitary tumors, although the clinical picture in this case is one of hyperthyroidism.

Thyroid hormone resistance ranges from euthyroid and clinically transparent to profoundly hypothyroid, and different organs in the same patient may show different sensitivities to thyroid hormone. Clinical features vary, depending on the strength of thyroid hormone resistance.

Early emergence of resistance (as would be expected in someone with an inherited thyroid hormone receptor abnormality) leads to developmental problems, including:

• short stature
• mental or learning disabilities (including attention deficits).

In a study of 18 families with strong history of generalized resistance to thyroid hormone, 70% of affected children met diagnostic criteria for attention-deficit/hyperactivity disorder.¹²

Box 2

Box 3

Laboratory screening

TSH and thyroid hormones. The basic thyroid screen is a combination of serum levels of TSH (“sensitive TSH”) and free thyroid hormones.

TSH has a circadian rhythm, with a nocturnal surge amounting to a 50% to 200% increase over daytime levels, beginning at around 6 to 8 PM. Peak TSH pulsatile activity and levels are seen after sleep begins—usually after midnight—with trough levels and fewest TSH pulses in late morning and early afternoon.^13,14 This rhythm implies that the most accurate TSH measurement may be obtained by drawing blood in the morning before 9 AM. I have seen subclinical hypothyroidism missed when clinicians relied on afternoon TSH levels.

In general medicine, TSH alone frequently is used as a routine screening tool. In psychiatric practice, however, I recommend supplementing TSH with free T3 and free T4 because thyroid system dysfunction is frequent in psychiatric syndromes. If laboratory costs are a concern, free T4 with TSH usually suffices for initial screening.

Although the unbound, free fractions of T3 and T4 are of primary interest, total T4 and total T3 are necessary to assess the thyroid gland’s synthetic capacity. When clinical evidence suggests abnormal thyroid hormone function, order repeated or serial biochemical testing. Marginal biochemical results also mandate repeat thyroid function studies, expanded to include:

• total thyroid hormone concentrations (ideally T4 and T3)
• antithyroid antibodies
• serum cholesterol
• prolactin.

Antithyroid antibodies. Obtain antithyroglobulin and antithyroid microsomal antibody titers if:

• thyroid hormone indices are abnormal or marginal—in either direction
• or the patient now has, has had, or has a family history of autoimmune-mediated symptoms, such as lupus erythematosus or rheumatoid arthritis.

Negative or low antithyroid autoantibody titers do not rule out thyroiditis as a cause of hypothyroidism, as these titers are most likely to be generated during periods of active inflammation.

Many autoantibodies react with thyroid-related elements. Most clinical laboratories can quantify antibodies directed against thyroid peroxidase—also called antimicrosomal antibodies—and thyroglobulin. The presence of these antibodies is associated with thyroid inflammation and a risk of progression to thyroid failure and hypothyroidism.

Other laboratory findings of hypothyroidism include hypercholesterolemia, mild hyperprolactinemia, and types of anemia (including iron-deficiency anemia with low ferritin levels).

Related resources

• American Thyroid Association. www.thyroid.org.
• Dunn JT. Guarding our nation’s thyroid health. J Clin Endocrinol Metab 2001;872:486-8.
• Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-55.
• Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biol Psychiatry 2006;60(5):500-6.

Methamphetamine abuse has spread to every region of the United States in the past 10 years (Table 1).¹ Its long-lasting, difficult-to-treat medical effects destroy lives and create psychiatric and physical comorbidities that confound clinicians in emergency rooms and community practice settings.

This first in a series of two articles describes methamphetamine’s growing use and offers guidance to identify abusers and manage acute “meth” intoxication. Methamphetamine-abusing patients can appear in any area of acute psychiatric practice—during emergency department (ED) evaluations, medical-surgical consultations, and inpatient psychiatric admissions. Using case examples, we describe key clinical principles to help you assess patients in each of these settings.

Table 1

10-year growth in hospitalization rates
for methamphetamine/amphetamine use*

Scourge of the Heartland

A stimulant first synthesized in Japan,² methamphetamine is the primary drug of abuse in Asia³ and the leading drug threat in the United States, according to U.S. law enforcement officials.⁴ Although most methamphetamine used in the United States is manufactured in “super-labs” along the U.S.-Mexican border,⁴ the drug is also easily made from common ingredients in small-scale home laboratories.

These smaller domestic “meth labs” have devastated rural communities and altered demographic patterns of methamphetamine abuse (Figure 1).⁵ Two aspects of rural life—relative isolation and availability of ingredients for production—proved critical in the initial spread of methamphetamine production and use in the United States. As a result, production by smaller labs is being targeted by state and federal law enforcement officers, who have had some success in eradicating this scourge (Box 1, Figure 2).^6-9

Figure 1 Substance abuse treatment admission rates
for methamphetamine-related diagnoses

Substance abuse treatment centers in rural areas had the highest admission rates for methamphetamine/amphetamine-related diagnoses in 2004. Admission rates in nonmetropolitan regions containing cities with populations >10,000 were triple those of suburbs, nearly twice those of big cities, and twice the U.S. average.

Source: Reference 5

Figure 2 Methamphetamine clandestine laboratory incidents,* 2005

* Incidents include chemicals, contaminated glass, and equipment used in methamphetamine production found by law enforcement agencies at laboratories or dump sites.

Source: Drug Enforcement Administration database, reference 9Box 1

Symptoms of ‘Meth’ Use

Physiologic effects. Methamphetamine is taken because it induces euphoria, anorexia, and increased energy, sexual stimulation, and alertness. Initial use evolves into abuse because of the drug’s highly addictive properties. Available in multiple forms and carrying a variety of labels (see Related resources), methamphetamine causes CNS release of monoamines—particularly dopamine—and damages dopaminergic neurons in the striatum and serotonergic neurons in the frontal lobes, striatum, and hippocampus.^10,11

Through sympathetic nervous system activation, methamphetamine can cause reversible or irreversible damage to organ systems (Table 2).^12-17

Table 2

Physiologic signs of methamphetamine abuse

Psychiatric effects. Methamphetamine abusers frequently report depressive symptoms, including irritability, anxiety, social isolation, and suicidal ideation.^10,18 These patients may show:

• signs of psychosis, including paranoia, hallucinations, and homicidal thoughts
• neurocognitive changes, including poor attention, impaired verbal memory, and decreased executive functioning.¹⁹

Agitation is frequent, and its severity appears to correlate directly with methamphetamine blood levels.²⁰ Violent behavior is common. In 1,016 previous users, 40% of men and 46% of women described difficulty controlling their behavior when under methamphetamine’s influence.¹⁸

In acute clinical practice, differentiating a primary thought disorder from methamphetamine-induced psychosis is challenging—especially when a patient shows signs of both.²¹ Methamphetamine also can contribute profoundly to depressive and anxiety disorders. Users may experience residual psychotic symptoms years after the original abuse ends, particularly when stressed. Their positive and negative symptoms are strikingly similar to those seen in schizophrenia.²¹

Longitudinal illness course, recent history, collateral information, and laboratory and physical data may all inform clinical presentations and comorbidity.

Emergent Evaluation

Gathering data. Police bring Mr. J, age 22, to the ED after his parents said he talked about killing himself and the mother of his 4-year-old child. Police report that Mr. J’s parents said he and his friends abuse methamphetamine, but no first-hand information is available.

Disheveled and uncooperative, Mr. J threatens to harm ED staff. His speech is pressured, and he appears to be responding to internal stimuli. Vital signs include temperature 37.8° C, pulse rate 105 bpm, blood pressure 140/85 mm Hg, and respiration rate 18 breaths per minute.

Mr. J refuses to provide blood or urine for drug screening or to provide a history to the ED physician. He attempts to walk out and is placed in restraints after he tries to punch the ED security officer.

Options for containing uncooperative and agitated patients such as Mr. J are extremely limited, and the overriding concern with violently intoxicated patients is to minimize damage to self, others, and property. Methamphetamine abusers have a propensity for impulsivity and violence;¹⁸ many are brought to the hospital by police and have criminal histories.¹ In emergent evaluation, begin by searching patients and their belongings for weapons.

Because laboratory results and patient history are not immediately available, methamphetamine abuse often is not included in the initial differential diagnosis—particularly for patients with pre-existing primary affective or psychotic disorders. It is critical to remember that methamphetamine abuse might be complicating a patient’s psychiatric presentation.

Managing agitation. When agitation is prominent, secure the patient in a quiet room to reduce stimulation. Have on hand adequate staffing and benzodiazepines, antipsychotics, or both.

In theory, using an antipsychotic to control methamphetamine-induced agitation is problematic because synergy between the two agents might adversely affect cardiac function.¹⁵ On the other hand, acute treatment of agitation often leads to salutary declines in pulse rate, blood pressure, respiration rate, and body temperature.

Box 2

Evidence on treating methamphetamine-induced agitation is limited (Box 2).^22-26 Before you prescribe any medication, keep in mind its side effect profile, the patient’s age and physical condition, and the possibility that other substances might be contributing to emergent presentations.

We have repeatedly and effectively treated acutely agitated patients in the ED with haloperidol and lorazepam without observing adverse effects. Psychiatrists generally favor haloperidol and lorazepam over droperidol and midazolam. When a patient can cooperate with treatment, we recommend an ECG to rule out prolonged QTc interval, an uncommon complication. Telemetry and a cardiology consultation are indicated with a QTc interval >450 msec or >25% over previous ECGs, particularly if you plan to continue haloperidol treatment.²⁷

Physical examination. Because methamphetamine use can cause substantial physical morbidity, we recommend a thorough physical exam aimed at identifying its stigmata (Table 2). Look especially for injuries resulting from violence, and test for sexually-transmitted diseases. Drug testing in the ED is essential to diagnosis and for planning treatment (Box 3).^28,29

Medical-Surgical Consultation

Ensuring safety. Ms. A, age 41, is admitted to the trauma surgery service after a motor vehicle accident in which she was the driver. She has long-standing methamphetamine dependence and is severely agitated. Urine drug testing is positive for methamphetamine, marijuana, and alcohol. Her alcohol serum level of 165 mg/dL exceeds the legal threshold for intoxication.

Tibial and fibular fractures sustained in the car accident require open reduction and internal fixation. On the postsurgical floor 2 days later, Ms. A remains “extremely irritable, dysphoric, and suicidal,” according to the trauma surgery consultation. Staff is concerned about her boyfriend’s behavior: “We think he’s using drugs and might be bringing her drugs.”

Understanding Ms. A’s behavior requires us to consider a broad range of diagnostic contributors, including:

• untreated withdrawal from alcohol or other drugs
• delirium from ongoing effects of the trauma or corrective operation
• inadequate pain control, particularly given her history of substance dependence
• psychiatric comorbidity.

Management includes:

• monitoring for withdrawal and treating it if symptoms emerge
• identifying and minimizing medical factors contributing to confusion, and medicating agitation with psychotropics
• providing adequate analgesia, mindful that dosing may need to be aggressive—particularly if the abused substances include narcotics
• assessing for pre-existing and methamphetamine-induced psychiatric disorders.

If the patient is cognitively able to cooperate, perform a thorough suicide assessment and provide initial supportive and cognitive-behavioral therapy to target suicidal behavior. Consider one-to-one monitoring, depending on the potential for deliberate self-injury, and guard against impulsive actions occurring in a drug- or treatment-induced delirium that could endanger the patient or staff.

A one-to-one monitor also can watch for smuggled contraband. When hospitalized, patients who are chronic substance abusers are prone to continue using illicit substances smuggled in by associates, such as the boyfriend in this case. Consider further testing for illicit drugs if you suspect smuggling.

Acute Psychiatric Inpatient

Initial diagnosis and treatment planning. Miss G, age 23 and homeless, is admitted directly to the inpatient psychiatric unit from an urgent care clinic. She reports being “depressed and suicidal.” An intermittent methamphetamine abuser, she says she last used the drug the previous day.

Miss G reveals that she is on probation for forged checks and drug use. She believes she failed a random urinalysis given earlier in the day as a condition of her probation, and she fears being sent back to jail. Her history includes childhood sexual abuse and emotional abuse in a relationship that ended the previous year.

Box 3

Physical examination shows multiple erythematous excoriations on her arms from repetitive picking at her skin, poor dentition, and cachexia. She reports multiple recent sexual partners without using condoms. She cannot remember when she last menstruated, and she doesn’t recall ever being tested for sexually transmitted disease.

As in any medical setting involving methamphetamine abusers, acute management of psychiatric inpatients includes careful attention to methamphetamine-related physical conditions—in Miss G’s case possible sexually transmitted diseases, pregnancy, cellulitis, and dental disease.

Mood and anxiety disorders. Methamphetamine users may present with depressive symptoms and suicidality.^18,30 In a study of Taiwanese methamphetamine abusers who had recently quit the drug, depressive symptoms were common on cessation but often resolved without antidepressants within 2 to 3 weeks.³⁰ Evidence on antidepressant use in the methamphetamine-dependent patient is limited, and the existing studies have yielded conflicting results (as we will detail in part 2 of this article).

For patients previously diagnosed with mood or anxiety disorders, do not restart psychotropics until you have considered how methamphetamine use is contributing to the immediate presentation. We recommend initial observation for several weeks before starting an antidepressant if there is no pre-methamphetamine history of mood or anxiety symptoms.

Psychosocial treatments. Involve social services in assessing the patient’s need for community resources. Miss G’s ability to benefit from these programs will depend on her cognitive capacity, education level, trauma history, and comorbid psychiatric illness.

For patients who relapse to methamphetamine use, previous successful treatment and abstinence may be a hopeful prognostic sign and warrant referral to a program for recidivists. The patient’s legal status may limit some options in the community but open others in the criminal justice system.

Methamphetamine users often have multiple problems that require attention. For example, compared with other mothers under investigation by child welfare services in California, methamphetamine-abusing mothers were younger and less educated on average, less likely to have had substance-abuse treatment, and more likely to have criminal records.³¹ These findings underscore the challenge of coordinating a response that integrates separate and complex systems—psychiatric/substance abuse treatment, child welfare, and criminal justice.

Related resources

• Methresources. Web site pooling information from multiple agencies for communities, law enforcement, and policy makers. www.methresources.gov.
• Methamphetamine. National drug threat assessment, with information on methamphetamine production, trafficking, and patterns of use. U.S. Department of Justice. Drug Enforcement Administration. www.dea.gov/concern/18862/meth.htm.
• Substance Abuse and Mental Health Services Administration. Drug and Alcohol Services Information System. Trends in methamphetamine/amphetamine admissions to treatment: 1993-2003. The DASIS Report 2006; Issue 9. www.oas.samhsa.gov/2k6/methTX/methTX.pdf.

Drug brand names

• Droperidol • Inapsine
• Haloperidol • Haldol
• Lorazepam • Ativan
• Midazolam • Versed

Disclosure

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

Methamphetamine abuse has spread to every region of the United States in the past 10 years (Table 1).¹ Its long-lasting, difficult-to-treat medical effects destroy lives and create psychiatric and physical comorbidities that confound clinicians in emergency rooms and community practice settings.

This first in a series of two articles describes methamphetamine’s growing use and offers guidance to identify abusers and manage acute “meth” intoxication. Methamphetamine-abusing patients can appear in any area of acute psychiatric practice—during emergency department (ED) evaluations, medical-surgical consultations, and inpatient psychiatric admissions. Using case examples, we describe key clinical principles to help you assess patients in each of these settings.

Table 1

10-year growth in hospitalization rates
for methamphetamine/amphetamine use*

Scourge of the Heartland

A stimulant first synthesized in Japan,² methamphetamine is the primary drug of abuse in Asia³ and the leading drug threat in the United States, according to U.S. law enforcement officials.⁴ Although most methamphetamine used in the United States is manufactured in “super-labs” along the U.S.-Mexican border,⁴ the drug is also easily made from common ingredients in small-scale home laboratories.

These smaller domestic “meth labs” have devastated rural communities and altered demographic patterns of methamphetamine abuse (Figure 1).⁵ Two aspects of rural life—relative isolation and availability of ingredients for production—proved critical in the initial spread of methamphetamine production and use in the United States. As a result, production by smaller labs is being targeted by state and federal law enforcement officers, who have had some success in eradicating this scourge (Box 1, Figure 2).^6-9

Figure 1 Substance abuse treatment admission rates
for methamphetamine-related diagnoses

Substance abuse treatment centers in rural areas had the highest admission rates for methamphetamine/amphetamine-related diagnoses in 2004. Admission rates in nonmetropolitan regions containing cities with populations >10,000 were triple those of suburbs, nearly twice those of big cities, and twice the U.S. average.

Source: Reference 5

Figure 2 Methamphetamine clandestine laboratory incidents,* 2005

* Incidents include chemicals, contaminated glass, and equipment used in methamphetamine production found by law enforcement agencies at laboratories or dump sites.

Source: Drug Enforcement Administration database, reference 9Box 1

Symptoms of ‘Meth’ Use

Physiologic effects. Methamphetamine is taken because it induces euphoria, anorexia, and increased energy, sexual stimulation, and alertness. Initial use evolves into abuse because of the drug’s highly addictive properties. Available in multiple forms and carrying a variety of labels (see Related resources), methamphetamine causes CNS release of monoamines—particularly dopamine—and damages dopaminergic neurons in the striatum and serotonergic neurons in the frontal lobes, striatum, and hippocampus.^10,11

Through sympathetic nervous system activation, methamphetamine can cause reversible or irreversible damage to organ systems (Table 2).^12-17

Table 2

Physiologic signs of methamphetamine abuse

Psychiatric effects. Methamphetamine abusers frequently report depressive symptoms, including irritability, anxiety, social isolation, and suicidal ideation.^10,18 These patients may show:

• signs of psychosis, including paranoia, hallucinations, and homicidal thoughts
• neurocognitive changes, including poor attention, impaired verbal memory, and decreased executive functioning.¹⁹

Agitation is frequent, and its severity appears to correlate directly with methamphetamine blood levels.²⁰ Violent behavior is common. In 1,016 previous users, 40% of men and 46% of women described difficulty controlling their behavior when under methamphetamine’s influence.¹⁸

In acute clinical practice, differentiating a primary thought disorder from methamphetamine-induced psychosis is challenging—especially when a patient shows signs of both.²¹ Methamphetamine also can contribute profoundly to depressive and anxiety disorders. Users may experience residual psychotic symptoms years after the original abuse ends, particularly when stressed. Their positive and negative symptoms are strikingly similar to those seen in schizophrenia.²¹

Longitudinal illness course, recent history, collateral information, and laboratory and physical data may all inform clinical presentations and comorbidity.

Emergent Evaluation

Gathering data. Police bring Mr. J, age 22, to the ED after his parents said he talked about killing himself and the mother of his 4-year-old child. Police report that Mr. J’s parents said he and his friends abuse methamphetamine, but no first-hand information is available.

Disheveled and uncooperative, Mr. J threatens to harm ED staff. His speech is pressured, and he appears to be responding to internal stimuli. Vital signs include temperature 37.8° C, pulse rate 105 bpm, blood pressure 140/85 mm Hg, and respiration rate 18 breaths per minute.

Mr. J refuses to provide blood or urine for drug screening or to provide a history to the ED physician. He attempts to walk out and is placed in restraints after he tries to punch the ED security officer.

Options for containing uncooperative and agitated patients such as Mr. J are extremely limited, and the overriding concern with violently intoxicated patients is to minimize damage to self, others, and property. Methamphetamine abusers have a propensity for impulsivity and violence;¹⁸ many are brought to the hospital by police and have criminal histories.¹ In emergent evaluation, begin by searching patients and their belongings for weapons.

Because laboratory results and patient history are not immediately available, methamphetamine abuse often is not included in the initial differential diagnosis—particularly for patients with pre-existing primary affective or psychotic disorders. It is critical to remember that methamphetamine abuse might be complicating a patient’s psychiatric presentation.

Managing agitation. When agitation is prominent, secure the patient in a quiet room to reduce stimulation. Have on hand adequate staffing and benzodiazepines, antipsychotics, or both.

In theory, using an antipsychotic to control methamphetamine-induced agitation is problematic because synergy between the two agents might adversely affect cardiac function.¹⁵ On the other hand, acute treatment of agitation often leads to salutary declines in pulse rate, blood pressure, respiration rate, and body temperature.

Box 2

Evidence on treating methamphetamine-induced agitation is limited (Box 2).^22-26 Before you prescribe any medication, keep in mind its side effect profile, the patient’s age and physical condition, and the possibility that other substances might be contributing to emergent presentations.

We have repeatedly and effectively treated acutely agitated patients in the ED with haloperidol and lorazepam without observing adverse effects. Psychiatrists generally favor haloperidol and lorazepam over droperidol and midazolam. When a patient can cooperate with treatment, we recommend an ECG to rule out prolonged QTc interval, an uncommon complication. Telemetry and a cardiology consultation are indicated with a QTc interval >450 msec or >25% over previous ECGs, particularly if you plan to continue haloperidol treatment.²⁷

Physical examination. Because methamphetamine use can cause substantial physical morbidity, we recommend a thorough physical exam aimed at identifying its stigmata (Table 2). Look especially for injuries resulting from violence, and test for sexually-transmitted diseases. Drug testing in the ED is essential to diagnosis and for planning treatment (Box 3).^28,29

Medical-Surgical Consultation

Ensuring safety. Ms. A, age 41, is admitted to the trauma surgery service after a motor vehicle accident in which she was the driver. She has long-standing methamphetamine dependence and is severely agitated. Urine drug testing is positive for methamphetamine, marijuana, and alcohol. Her alcohol serum level of 165 mg/dL exceeds the legal threshold for intoxication.

Tibial and fibular fractures sustained in the car accident require open reduction and internal fixation. On the postsurgical floor 2 days later, Ms. A remains “extremely irritable, dysphoric, and suicidal,” according to the trauma surgery consultation. Staff is concerned about her boyfriend’s behavior: “We think he’s using drugs and might be bringing her drugs.”

Understanding Ms. A’s behavior requires us to consider a broad range of diagnostic contributors, including:

• untreated withdrawal from alcohol or other drugs
• delirium from ongoing effects of the trauma or corrective operation
• inadequate pain control, particularly given her history of substance dependence
• psychiatric comorbidity.

Management includes:

• monitoring for withdrawal and treating it if symptoms emerge
• identifying and minimizing medical factors contributing to confusion, and medicating agitation with psychotropics
• providing adequate analgesia, mindful that dosing may need to be aggressive—particularly if the abused substances include narcotics
• assessing for pre-existing and methamphetamine-induced psychiatric disorders.

If the patient is cognitively able to cooperate, perform a thorough suicide assessment and provide initial supportive and cognitive-behavioral therapy to target suicidal behavior. Consider one-to-one monitoring, depending on the potential for deliberate self-injury, and guard against impulsive actions occurring in a drug- or treatment-induced delirium that could endanger the patient or staff.

A one-to-one monitor also can watch for smuggled contraband. When hospitalized, patients who are chronic substance abusers are prone to continue using illicit substances smuggled in by associates, such as the boyfriend in this case. Consider further testing for illicit drugs if you suspect smuggling.

Acute Psychiatric Inpatient

Initial diagnosis and treatment planning. Miss G, age 23 and homeless, is admitted directly to the inpatient psychiatric unit from an urgent care clinic. She reports being “depressed and suicidal.” An intermittent methamphetamine abuser, she says she last used the drug the previous day.

Miss G reveals that she is on probation for forged checks and drug use. She believes she failed a random urinalysis given earlier in the day as a condition of her probation, and she fears being sent back to jail. Her history includes childhood sexual abuse and emotional abuse in a relationship that ended the previous year.

Box 3

Physical examination shows multiple erythematous excoriations on her arms from repetitive picking at her skin, poor dentition, and cachexia. She reports multiple recent sexual partners without using condoms. She cannot remember when she last menstruated, and she doesn’t recall ever being tested for sexually transmitted disease.

As in any medical setting involving methamphetamine abusers, acute management of psychiatric inpatients includes careful attention to methamphetamine-related physical conditions—in Miss G’s case possible sexually transmitted diseases, pregnancy, cellulitis, and dental disease.

Mood and anxiety disorders. Methamphetamine users may present with depressive symptoms and suicidality.^18,30 In a study of Taiwanese methamphetamine abusers who had recently quit the drug, depressive symptoms were common on cessation but often resolved without antidepressants within 2 to 3 weeks.³⁰ Evidence on antidepressant use in the methamphetamine-dependent patient is limited, and the existing studies have yielded conflicting results (as we will detail in part 2 of this article).

For patients previously diagnosed with mood or anxiety disorders, do not restart psychotropics until you have considered how methamphetamine use is contributing to the immediate presentation. We recommend initial observation for several weeks before starting an antidepressant if there is no pre-methamphetamine history of mood or anxiety symptoms.

Psychosocial treatments. Involve social services in assessing the patient’s need for community resources. Miss G’s ability to benefit from these programs will depend on her cognitive capacity, education level, trauma history, and comorbid psychiatric illness.

For patients who relapse to methamphetamine use, previous successful treatment and abstinence may be a hopeful prognostic sign and warrant referral to a program for recidivists. The patient’s legal status may limit some options in the community but open others in the criminal justice system.

Methamphetamine users often have multiple problems that require attention. For example, compared with other mothers under investigation by child welfare services in California, methamphetamine-abusing mothers were younger and less educated on average, less likely to have had substance-abuse treatment, and more likely to have criminal records.³¹ These findings underscore the challenge of coordinating a response that integrates separate and complex systems—psychiatric/substance abuse treatment, child welfare, and criminal justice.

Related resources

• Methresources. Web site pooling information from multiple agencies for communities, law enforcement, and policy makers. www.methresources.gov.
• Methamphetamine. National drug threat assessment, with information on methamphetamine production, trafficking, and patterns of use. U.S. Department of Justice. Drug Enforcement Administration. www.dea.gov/concern/18862/meth.htm.
• Substance Abuse and Mental Health Services Administration. Drug and Alcohol Services Information System. Trends in methamphetamine/amphetamine admissions to treatment: 1993-2003. The DASIS Report 2006; Issue 9. www.oas.samhsa.gov/2k6/methTX/methTX.pdf.

Drug brand names

• Droperidol • Inapsine
• Haloperidol • Haldol
• Lorazepam • Ativan
• Midazolam • Versed

Disclosure

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

Methamphetamine abuse has spread to every region of the United States in the past 10 years (Table 1).¹ Its long-lasting, difficult-to-treat medical effects destroy lives and create psychiatric and physical comorbidities that confound clinicians in emergency rooms and community practice settings.

This first in a series of two articles describes methamphetamine’s growing use and offers guidance to identify abusers and manage acute “meth” intoxication. Methamphetamine-abusing patients can appear in any area of acute psychiatric practice—during emergency department (ED) evaluations, medical-surgical consultations, and inpatient psychiatric admissions. Using case examples, we describe key clinical principles to help you assess patients in each of these settings.

Table 1

10-year growth in hospitalization rates
for methamphetamine/amphetamine use*

Scourge of the Heartland

A stimulant first synthesized in Japan,² methamphetamine is the primary drug of abuse in Asia³ and the leading drug threat in the United States, according to U.S. law enforcement officials.⁴ Although most methamphetamine used in the United States is manufactured in “super-labs” along the U.S.-Mexican border,⁴ the drug is also easily made from common ingredients in small-scale home laboratories.

These smaller domestic “meth labs” have devastated rural communities and altered demographic patterns of methamphetamine abuse (Figure 1).⁵ Two aspects of rural life—relative isolation and availability of ingredients for production—proved critical in the initial spread of methamphetamine production and use in the United States. As a result, production by smaller labs is being targeted by state and federal law enforcement officers, who have had some success in eradicating this scourge (Box 1, Figure 2).^6-9

Figure 1 Substance abuse treatment admission rates
for methamphetamine-related diagnoses

Substance abuse treatment centers in rural areas had the highest admission rates for methamphetamine/amphetamine-related diagnoses in 2004. Admission rates in nonmetropolitan regions containing cities with populations >10,000 were triple those of suburbs, nearly twice those of big cities, and twice the U.S. average.

Source: Reference 5

Figure 2 Methamphetamine clandestine laboratory incidents,* 2005

* Incidents include chemicals, contaminated glass, and equipment used in methamphetamine production found by law enforcement agencies at laboratories or dump sites.

Source: Drug Enforcement Administration database, reference 9Box 1

Symptoms of ‘Meth’ Use

Physiologic effects. Methamphetamine is taken because it induces euphoria, anorexia, and increased energy, sexual stimulation, and alertness. Initial use evolves into abuse because of the drug’s highly addictive properties. Available in multiple forms and carrying a variety of labels (see Related resources), methamphetamine causes CNS release of monoamines—particularly dopamine—and damages dopaminergic neurons in the striatum and serotonergic neurons in the frontal lobes, striatum, and hippocampus.^10,11

Through sympathetic nervous system activation, methamphetamine can cause reversible or irreversible damage to organ systems (Table 2).^12-17

Table 2

Physiologic signs of methamphetamine abuse

Psychiatric effects. Methamphetamine abusers frequently report depressive symptoms, including irritability, anxiety, social isolation, and suicidal ideation.^10,18 These patients may show:

• signs of psychosis, including paranoia, hallucinations, and homicidal thoughts
• neurocognitive changes, including poor attention, impaired verbal memory, and decreased executive functioning.¹⁹

Agitation is frequent, and its severity appears to correlate directly with methamphetamine blood levels.²⁰ Violent behavior is common. In 1,016 previous users, 40% of men and 46% of women described difficulty controlling their behavior when under methamphetamine’s influence.¹⁸

In acute clinical practice, differentiating a primary thought disorder from methamphetamine-induced psychosis is challenging—especially when a patient shows signs of both.²¹ Methamphetamine also can contribute profoundly to depressive and anxiety disorders. Users may experience residual psychotic symptoms years after the original abuse ends, particularly when stressed. Their positive and negative symptoms are strikingly similar to those seen in schizophrenia.²¹

Longitudinal illness course, recent history, collateral information, and laboratory and physical data may all inform clinical presentations and comorbidity.

Emergent Evaluation

Gathering data. Police bring Mr. J, age 22, to the ED after his parents said he talked about killing himself and the mother of his 4-year-old child. Police report that Mr. J’s parents said he and his friends abuse methamphetamine, but no first-hand information is available.

Disheveled and uncooperative, Mr. J threatens to harm ED staff. His speech is pressured, and he appears to be responding to internal stimuli. Vital signs include temperature 37.8° C, pulse rate 105 bpm, blood pressure 140/85 mm Hg, and respiration rate 18 breaths per minute.

Mr. J refuses to provide blood or urine for drug screening or to provide a history to the ED physician. He attempts to walk out and is placed in restraints after he tries to punch the ED security officer.

Options for containing uncooperative and agitated patients such as Mr. J are extremely limited, and the overriding concern with violently intoxicated patients is to minimize damage to self, others, and property. Methamphetamine abusers have a propensity for impulsivity and violence;¹⁸ many are brought to the hospital by police and have criminal histories.¹ In emergent evaluation, begin by searching patients and their belongings for weapons.

Because laboratory results and patient history are not immediately available, methamphetamine abuse often is not included in the initial differential diagnosis—particularly for patients with pre-existing primary affective or psychotic disorders. It is critical to remember that methamphetamine abuse might be complicating a patient’s psychiatric presentation.

Managing agitation. When agitation is prominent, secure the patient in a quiet room to reduce stimulation. Have on hand adequate staffing and benzodiazepines, antipsychotics, or both.

In theory, using an antipsychotic to control methamphetamine-induced agitation is problematic because synergy between the two agents might adversely affect cardiac function.¹⁵ On the other hand, acute treatment of agitation often leads to salutary declines in pulse rate, blood pressure, respiration rate, and body temperature.

Box 2

Evidence on treating methamphetamine-induced agitation is limited (Box 2).^22-26 Before you prescribe any medication, keep in mind its side effect profile, the patient’s age and physical condition, and the possibility that other substances might be contributing to emergent presentations.

We have repeatedly and effectively treated acutely agitated patients in the ED with haloperidol and lorazepam without observing adverse effects. Psychiatrists generally favor haloperidol and lorazepam over droperidol and midazolam. When a patient can cooperate with treatment, we recommend an ECG to rule out prolonged QTc interval, an uncommon complication. Telemetry and a cardiology consultation are indicated with a QTc interval >450 msec or >25% over previous ECGs, particularly if you plan to continue haloperidol treatment.²⁷

Physical examination. Because methamphetamine use can cause substantial physical morbidity, we recommend a thorough physical exam aimed at identifying its stigmata (Table 2). Look especially for injuries resulting from violence, and test for sexually-transmitted diseases. Drug testing in the ED is essential to diagnosis and for planning treatment (Box 3).^28,29

Medical-Surgical Consultation

Ensuring safety. Ms. A, age 41, is admitted to the trauma surgery service after a motor vehicle accident in which she was the driver. She has long-standing methamphetamine dependence and is severely agitated. Urine drug testing is positive for methamphetamine, marijuana, and alcohol. Her alcohol serum level of 165 mg/dL exceeds the legal threshold for intoxication.

Tibial and fibular fractures sustained in the car accident require open reduction and internal fixation. On the postsurgical floor 2 days later, Ms. A remains “extremely irritable, dysphoric, and suicidal,” according to the trauma surgery consultation. Staff is concerned about her boyfriend’s behavior: “We think he’s using drugs and might be bringing her drugs.”

Understanding Ms. A’s behavior requires us to consider a broad range of diagnostic contributors, including:

• untreated withdrawal from alcohol or other drugs
• delirium from ongoing effects of the trauma or corrective operation
• inadequate pain control, particularly given her history of substance dependence
• psychiatric comorbidity.

Management includes:

• monitoring for withdrawal and treating it if symptoms emerge
• identifying and minimizing medical factors contributing to confusion, and medicating agitation with psychotropics
• providing adequate analgesia, mindful that dosing may need to be aggressive—particularly if the abused substances include narcotics
• assessing for pre-existing and methamphetamine-induced psychiatric disorders.

If the patient is cognitively able to cooperate, perform a thorough suicide assessment and provide initial supportive and cognitive-behavioral therapy to target suicidal behavior. Consider one-to-one monitoring, depending on the potential for deliberate self-injury, and guard against impulsive actions occurring in a drug- or treatment-induced delirium that could endanger the patient or staff.

A one-to-one monitor also can watch for smuggled contraband. When hospitalized, patients who are chronic substance abusers are prone to continue using illicit substances smuggled in by associates, such as the boyfriend in this case. Consider further testing for illicit drugs if you suspect smuggling.

Acute Psychiatric Inpatient

Initial diagnosis and treatment planning. Miss G, age 23 and homeless, is admitted directly to the inpatient psychiatric unit from an urgent care clinic. She reports being “depressed and suicidal.” An intermittent methamphetamine abuser, she says she last used the drug the previous day.

Miss G reveals that she is on probation for forged checks and drug use. She believes she failed a random urinalysis given earlier in the day as a condition of her probation, and she fears being sent back to jail. Her history includes childhood sexual abuse and emotional abuse in a relationship that ended the previous year.

Box 3

Physical examination shows multiple erythematous excoriations on her arms from repetitive picking at her skin, poor dentition, and cachexia. She reports multiple recent sexual partners without using condoms. She cannot remember when she last menstruated, and she doesn’t recall ever being tested for sexually transmitted disease.

As in any medical setting involving methamphetamine abusers, acute management of psychiatric inpatients includes careful attention to methamphetamine-related physical conditions—in Miss G’s case possible sexually transmitted diseases, pregnancy, cellulitis, and dental disease.

Mood and anxiety disorders. Methamphetamine users may present with depressive symptoms and suicidality.^18,30 In a study of Taiwanese methamphetamine abusers who had recently quit the drug, depressive symptoms were common on cessation but often resolved without antidepressants within 2 to 3 weeks.³⁰ Evidence on antidepressant use in the methamphetamine-dependent patient is limited, and the existing studies have yielded conflicting results (as we will detail in part 2 of this article).

For patients previously diagnosed with mood or anxiety disorders, do not restart psychotropics until you have considered how methamphetamine use is contributing to the immediate presentation. We recommend initial observation for several weeks before starting an antidepressant if there is no pre-methamphetamine history of mood or anxiety symptoms.

Psychosocial treatments. Involve social services in assessing the patient’s need for community resources. Miss G’s ability to benefit from these programs will depend on her cognitive capacity, education level, trauma history, and comorbid psychiatric illness.

For patients who relapse to methamphetamine use, previous successful treatment and abstinence may be a hopeful prognostic sign and warrant referral to a program for recidivists. The patient’s legal status may limit some options in the community but open others in the criminal justice system.

Methamphetamine users often have multiple problems that require attention. For example, compared with other mothers under investigation by child welfare services in California, methamphetamine-abusing mothers were younger and less educated on average, less likely to have had substance-abuse treatment, and more likely to have criminal records.³¹ These findings underscore the challenge of coordinating a response that integrates separate and complex systems—psychiatric/substance abuse treatment, child welfare, and criminal justice.

Related resources

• Methresources. Web site pooling information from multiple agencies for communities, law enforcement, and policy makers. www.methresources.gov.
• Methamphetamine. National drug threat assessment, with information on methamphetamine production, trafficking, and patterns of use. U.S. Department of Justice. Drug Enforcement Administration. www.dea.gov/concern/18862/meth.htm.
• Substance Abuse and Mental Health Services Administration. Drug and Alcohol Services Information System. Trends in methamphetamine/amphetamine admissions to treatment: 1993-2003. The DASIS Report 2006; Issue 9. www.oas.samhsa.gov/2k6/methTX/methTX.pdf.

Drug brand names

• Droperidol • Inapsine
• Haloperidol • Haldol
• Lorazepam • Ativan
• Midazolam • Versed

Disclosure

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

Many findings of the Clinical Antipsychotic Trials of Intervention Effectiveness in schizophrenia (CATIE) were unexpected,^1,2 but one was arguably the most surprising. It was that schizophrenia patients showed similar rates of extrapyramidal symptoms (EPS), whether treated with a first-generation antipsychotic (FGA) or any of four second-generation antipsychotics (SGAs).

This finding in CATIE phase 1 runs contrary to the understanding that SGAs, compared with FGAs, provide a broader spectrum of efficacy with significantly fewer motor side effects. A substantial body of evidence and virtually all schizophrenia treatment guidelines^3-5 support this prevailing view.

Did earlier schizophrenia treatment studies misinform us, or was CATIE’s comparison of FGAs and SGAs “flawed”?^6,7 This article attempts to reconcile the divergent findings about antipsychotics and EPS and reveals a clinical pearl that suggests how to provide optimum antipsychotic therapy to schizophrenia patients.

What did catie find?

CATIE was a three-phase, 18-month, randomized controlled clinical trial designed to evaluate the effectiveness of five SGAs (risperidone, olanzapine, quetiapine, ziprasidone, and clozapine) and two FGAs (perphenazine and fluphenazine) in treating schizophrenia. Findings from phases 1 and 2 have been published or presented (Table 1),^2,8-9 and results from phase 3 are awaited.

Table 1

5 key findings from CATIE phases 1 and 2

CATIE phase 1 found no difference in efficacy, safety/tolerability, or effectiveness among perphenazine, risperidone, ziprasidone, and quetiapine. Soon-to-be-published data also will show no significant difference in cognitive effects among patients receiving perphenazine or any of four SGAs (risperidone, olanzapine, quetiapine, or ziprasidone).⁸ Because no FGA was used in CATIE phase 2,^9-11 its results added little to phase 1 observations about how “typical” and “atypical” antipsychotics compare.

‘Atypicals’ and EPS. By definition, a reduced tendency to cause EPS (such as parkinsonism, dystonia, akathisia, and akinesia) distinguishes SGAs from FGAs. In fact, SGAs were called “atypical” because they disproved the belief that EPS are an unavoidable consequence of drugs that produce an antipsychotic effect.^12,13 The CATIE trial’s inability to detect a difference in EPS rates between typical and atypical antipsychotics (Table 2)² is therefore the study’s most surprising finding.

Table 2

CATIE: Similar EPS rates with perphenazine and SGAs*

Making sense of catie

Most studies suggest consistent differences between FGAs and SGAs in risk of EPS and tardive dyskinesia.^14-16 One explanation for CATIE’s discrepant findings may be that the use of high-dose, high-potency haloperidol as the typical comparator in pre-CATIE studies magnified differences between FGAs and SGAs.^17,18

Conversely, CATIE researchers minimized this difference by studying a population of schizophrenia patients at an unusually low risk for EPS. The study design:

• assigned 231 patients with a history of tardive dyskinesia to an SGA, without the opportunity to be randomly assigned to an FGA
• excluded patients with first-episode schizophrenia
• enrolled patients who had been treated with antipsychotics for an average of 14 years without a history of significant adverse effects from study treatments.¹⁹

Just as prior studies might have exaggerated the EPS advantage for SGAs, CATIE might have minimized the FGA-SGA difference by studying a low-risk cohort in a way that reduced the trial’s ability to detect such differences.

Interpretation. How can we reconcile the absence of a difference between FGAs and SGAs in EPS liability in CATIE with the preponderance of data suggesting otherwise? It appears that SGAs may be less likely to cause EPS than FGAs, but this difference is not evident in all populations. Furthermore, SGAs and FGAs differ in their ability to provide an adequate antipsychotic effect without EPS.

Among FGAs, low-potency agents are less likely to cause EPS or require concomitant anticholinergics than high-potency agents. Among SGAs, the gradient of EPS liability appears to be risperidone > olanzapine, aripiprazole, ziprasidone > quetiapine > clozapine (Figure). Clinically, these pharmacologic differences interact with physiologic differences in EPS vulnerability—some patients are more liable to develop EPS than others. Individuals who are more susceptible to developing EPS are more likely to benefit from antipsychotics with lower EPS liability.

CATIE found no difference among the various FGAs and SGAs with regard to overall efficacy, effects on cognition, and occurrence of tardive dyskinesia in treating chronic schizophrenia. Perhaps it was CATIE’s failure to find a difference in EPS that explains its inability to demonstrate FGA-SGA differences in cognition and other effectiveness domains.

Figure Dose-response curves: Antipsychotic vs extrapyramidal effects

All FGAs and SGAs produce an equivalent antipsychotic effect (red), but they vary in the degree of separation between dosages at which their antipsychotic and extrapyramidal effects occur.

Source: Adapted from reference 13

What catie tells us

The exaggerated view of SGAs as uniformly more efficacious, safer, and better tolerated than FGAs needs to be revised. At the same time, however, the results of CATIE should not be over-interpreted. They tell us that if the four phase 1 SGAs and the FGA perphenazine are used at certain dosages in a particular manner in a specific schizophrenia population—chronic, moderately ill, without tardive dyskinesia—then no differences might be expected among these antipsychotics. But CATIE’s findings might not generalize beyond individuals with schizophrenia at low risk for EPS.

CATIE underlines the importance of achieving an adequate antipsychotic effect without EPS and without using anticholinergics. Clinical consequences of EPS extend beyond motor manifestations and include:

• worse cognition (bradyphrenia)
• worse negative symptoms (neuroleptic-induced deficit syndrome)
• worse depression and suicidality (neuroleptic dysphoria)
• higher risk of tardive dyskinesia.²⁰

SGAs’ presumed ability to provide broader efficacy—cognition, negative symptoms, dysphoria—and lower risk of tardive dyskinesia appears to be driven by their lower EPS liability in association with an equivalent antipsychotic effect. Evidence for an SGA advantage independent of this effect is weak.^21,22

Thus, CATIE’s inability to find an FGA-SGA difference in EPS might explain its failure to observe an FGA-SGA difference in cognition and other effectiveness domains.

The clinical pearl

Avoiding EPS and anticholinergics appears to be the key to improving cognition, dysphoria, and negative symptoms with FGAs and SGAs. SGAs’ ability to achieve an equivalent antipsychotic effect without EPS also seems related to their lower risk of tardive dyskinesia.

SGAs’ main advantage may be their greater ease of achieving an adequate antipsychotic effect without EPS or the need to add an anticholinergic to treat or prevent EPS. This comes from the broader separation between dosages at which SGAs produce their antipsychotic versus EPS effects, compared with FGAs (Figure).¹³

In clinical practice, then, we must achieve an adequate antipsychotic effect for our patients without EPS—whether we are using FGAs or SGAs—to obtain “atypical” benefits. The purported benefits of an “atypical” antipsychotic are not unique to a particular class of agents but relate to achieving a good antipsychotic effect without EPS—and the SGAs are better able to accomplish this than the FGAs.

Careful EPS monitoring is crucial to achieving optimal antipsychotic therapy. Reduced emphasis on EPS in the past decade (in awareness of EPS and training to detect symptoms) and overlap between behavioral aspects of EPS and psychopathology need to be addressed.

CATIE confirms clinical observations that:

• no antipsychotic is always superior
• schizophrenia therapy must be individualized.^23,24

Different agents are associated with different adverse effects, which can make achieving maximum efficacy and safety/tolerability challenging.

But differences among antipsychotics and heterogeneity in individual response and vulnerabilities may allow us to optimize treatment.

Different agents at different dosages may provide the best outcomes for individual patients, and the optimal agent and/or dosage can vary in the same patient at different stages of the illness. The CATIE trial contributes to evidence that guides our efforts to provide optimal antipsychotic treatment of schizophrenia (Table 3). Its “surprising” findings are most useful when considered in the context of the database to which it adds.²⁵

Table 3

Treating chronic schizophrenia: 4 clinical tips from CATIE

Related resources

• Tandon R. Comparative effectiveness of antipsychotics in the treatment of schizophrenia: What does CATIE tell us? Parts 1 and 2. Int Drug Ther Newsl 2006;41:51-8;67-74.
• Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. www.catie.unc.edu/schizophrenia.

Drug brand names

• Clozapine • Clozaril
• Fluphenazine • Permitil
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Risperidone • Risperdal
• Quetiapine • Seroquel
• Ziprasidone • Geodon

Disclosures

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

Many findings of the Clinical Antipsychotic Trials of Intervention Effectiveness in schizophrenia (CATIE) were unexpected,^1,2 but one was arguably the most surprising. It was that schizophrenia patients showed similar rates of extrapyramidal symptoms (EPS), whether treated with a first-generation antipsychotic (FGA) or any of four second-generation antipsychotics (SGAs).

This finding in CATIE phase 1 runs contrary to the understanding that SGAs, compared with FGAs, provide a broader spectrum of efficacy with significantly fewer motor side effects. A substantial body of evidence and virtually all schizophrenia treatment guidelines^3-5 support this prevailing view.

Did earlier schizophrenia treatment studies misinform us, or was CATIE’s comparison of FGAs and SGAs “flawed”?^6,7 This article attempts to reconcile the divergent findings about antipsychotics and EPS and reveals a clinical pearl that suggests how to provide optimum antipsychotic therapy to schizophrenia patients.

What did catie find?

CATIE was a three-phase, 18-month, randomized controlled clinical trial designed to evaluate the effectiveness of five SGAs (risperidone, olanzapine, quetiapine, ziprasidone, and clozapine) and two FGAs (perphenazine and fluphenazine) in treating schizophrenia. Findings from phases 1 and 2 have been published or presented (Table 1),^2,8-9 and results from phase 3 are awaited.

Table 1

5 key findings from CATIE phases 1 and 2

CATIE phase 1 found no difference in efficacy, safety/tolerability, or effectiveness among perphenazine, risperidone, ziprasidone, and quetiapine. Soon-to-be-published data also will show no significant difference in cognitive effects among patients receiving perphenazine or any of four SGAs (risperidone, olanzapine, quetiapine, or ziprasidone).⁸ Because no FGA was used in CATIE phase 2,^9-11 its results added little to phase 1 observations about how “typical” and “atypical” antipsychotics compare.

‘Atypicals’ and EPS. By definition, a reduced tendency to cause EPS (such as parkinsonism, dystonia, akathisia, and akinesia) distinguishes SGAs from FGAs. In fact, SGAs were called “atypical” because they disproved the belief that EPS are an unavoidable consequence of drugs that produce an antipsychotic effect.^12,13 The CATIE trial’s inability to detect a difference in EPS rates between typical and atypical antipsychotics (Table 2)² is therefore the study’s most surprising finding.

Table 2

CATIE: Similar EPS rates with perphenazine and SGAs*

Making sense of catie

Most studies suggest consistent differences between FGAs and SGAs in risk of EPS and tardive dyskinesia.^14-16 One explanation for CATIE’s discrepant findings may be that the use of high-dose, high-potency haloperidol as the typical comparator in pre-CATIE studies magnified differences between FGAs and SGAs.^17,18

Conversely, CATIE researchers minimized this difference by studying a population of schizophrenia patients at an unusually low risk for EPS. The study design:

• assigned 231 patients with a history of tardive dyskinesia to an SGA, without the opportunity to be randomly assigned to an FGA
• excluded patients with first-episode schizophrenia
• enrolled patients who had been treated with antipsychotics for an average of 14 years without a history of significant adverse effects from study treatments.¹⁹

Just as prior studies might have exaggerated the EPS advantage for SGAs, CATIE might have minimized the FGA-SGA difference by studying a low-risk cohort in a way that reduced the trial’s ability to detect such differences.

Interpretation. How can we reconcile the absence of a difference between FGAs and SGAs in EPS liability in CATIE with the preponderance of data suggesting otherwise? It appears that SGAs may be less likely to cause EPS than FGAs, but this difference is not evident in all populations. Furthermore, SGAs and FGAs differ in their ability to provide an adequate antipsychotic effect without EPS.

Among FGAs, low-potency agents are less likely to cause EPS or require concomitant anticholinergics than high-potency agents. Among SGAs, the gradient of EPS liability appears to be risperidone > olanzapine, aripiprazole, ziprasidone > quetiapine > clozapine (Figure). Clinically, these pharmacologic differences interact with physiologic differences in EPS vulnerability—some patients are more liable to develop EPS than others. Individuals who are more susceptible to developing EPS are more likely to benefit from antipsychotics with lower EPS liability.

CATIE found no difference among the various FGAs and SGAs with regard to overall efficacy, effects on cognition, and occurrence of tardive dyskinesia in treating chronic schizophrenia. Perhaps it was CATIE’s failure to find a difference in EPS that explains its inability to demonstrate FGA-SGA differences in cognition and other effectiveness domains.

Figure Dose-response curves: Antipsychotic vs extrapyramidal effects

All FGAs and SGAs produce an equivalent antipsychotic effect (red), but they vary in the degree of separation between dosages at which their antipsychotic and extrapyramidal effects occur.

Source: Adapted from reference 13

What catie tells us

The exaggerated view of SGAs as uniformly more efficacious, safer, and better tolerated than FGAs needs to be revised. At the same time, however, the results of CATIE should not be over-interpreted. They tell us that if the four phase 1 SGAs and the FGA perphenazine are used at certain dosages in a particular manner in a specific schizophrenia population—chronic, moderately ill, without tardive dyskinesia—then no differences might be expected among these antipsychotics. But CATIE’s findings might not generalize beyond individuals with schizophrenia at low risk for EPS.

CATIE underlines the importance of achieving an adequate antipsychotic effect without EPS and without using anticholinergics. Clinical consequences of EPS extend beyond motor manifestations and include:

• worse cognition (bradyphrenia)
• worse negative symptoms (neuroleptic-induced deficit syndrome)
• worse depression and suicidality (neuroleptic dysphoria)
• higher risk of tardive dyskinesia.²⁰

SGAs’ presumed ability to provide broader efficacy—cognition, negative symptoms, dysphoria—and lower risk of tardive dyskinesia appears to be driven by their lower EPS liability in association with an equivalent antipsychotic effect. Evidence for an SGA advantage independent of this effect is weak.^21,22

Thus, CATIE’s inability to find an FGA-SGA difference in EPS might explain its failure to observe an FGA-SGA difference in cognition and other effectiveness domains.

The clinical pearl

Avoiding EPS and anticholinergics appears to be the key to improving cognition, dysphoria, and negative symptoms with FGAs and SGAs. SGAs’ ability to achieve an equivalent antipsychotic effect without EPS also seems related to their lower risk of tardive dyskinesia.

SGAs’ main advantage may be their greater ease of achieving an adequate antipsychotic effect without EPS or the need to add an anticholinergic to treat or prevent EPS. This comes from the broader separation between dosages at which SGAs produce their antipsychotic versus EPS effects, compared with FGAs (Figure).¹³

In clinical practice, then, we must achieve an adequate antipsychotic effect for our patients without EPS—whether we are using FGAs or SGAs—to obtain “atypical” benefits. The purported benefits of an “atypical” antipsychotic are not unique to a particular class of agents but relate to achieving a good antipsychotic effect without EPS—and the SGAs are better able to accomplish this than the FGAs.

Careful EPS monitoring is crucial to achieving optimal antipsychotic therapy. Reduced emphasis on EPS in the past decade (in awareness of EPS and training to detect symptoms) and overlap between behavioral aspects of EPS and psychopathology need to be addressed.

CATIE confirms clinical observations that:

• no antipsychotic is always superior
• schizophrenia therapy must be individualized.^23,24

Different agents are associated with different adverse effects, which can make achieving maximum efficacy and safety/tolerability challenging.

But differences among antipsychotics and heterogeneity in individual response and vulnerabilities may allow us to optimize treatment.

Different agents at different dosages may provide the best outcomes for individual patients, and the optimal agent and/or dosage can vary in the same patient at different stages of the illness. The CATIE trial contributes to evidence that guides our efforts to provide optimal antipsychotic treatment of schizophrenia (Table 3). Its “surprising” findings are most useful when considered in the context of the database to which it adds.²⁵

Table 3

Treating chronic schizophrenia: 4 clinical tips from CATIE

Related resources

• Tandon R. Comparative effectiveness of antipsychotics in the treatment of schizophrenia: What does CATIE tell us? Parts 1 and 2. Int Drug Ther Newsl 2006;41:51-8;67-74.
• Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. www.catie.unc.edu/schizophrenia.

Drug brand names

• Clozapine • Clozaril
• Fluphenazine • Permitil
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Risperidone • Risperdal
• Quetiapine • Seroquel
• Ziprasidone • Geodon

Disclosures

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

Many findings of the Clinical Antipsychotic Trials of Intervention Effectiveness in schizophrenia (CATIE) were unexpected,^1,2 but one was arguably the most surprising. It was that schizophrenia patients showed similar rates of extrapyramidal symptoms (EPS), whether treated with a first-generation antipsychotic (FGA) or any of four second-generation antipsychotics (SGAs).

This finding in CATIE phase 1 runs contrary to the understanding that SGAs, compared with FGAs, provide a broader spectrum of efficacy with significantly fewer motor side effects. A substantial body of evidence and virtually all schizophrenia treatment guidelines^3-5 support this prevailing view.

Did earlier schizophrenia treatment studies misinform us, or was CATIE’s comparison of FGAs and SGAs “flawed”?^6,7 This article attempts to reconcile the divergent findings about antipsychotics and EPS and reveals a clinical pearl that suggests how to provide optimum antipsychotic therapy to schizophrenia patients.

What did catie find?

CATIE was a three-phase, 18-month, randomized controlled clinical trial designed to evaluate the effectiveness of five SGAs (risperidone, olanzapine, quetiapine, ziprasidone, and clozapine) and two FGAs (perphenazine and fluphenazine) in treating schizophrenia. Findings from phases 1 and 2 have been published or presented (Table 1),^2,8-9 and results from phase 3 are awaited.

Table 1

5 key findings from CATIE phases 1 and 2