Current Psychiatry

Dr. Shelley Sellinger’s article “Helping indigent patients obtain medications” (Pearls, Current Psychiatry, April 2005) is helpful for psychiatrists working with patients who lack pharmacy benefits. Not having the information handy or believing the process is too cumbersome may deter some clinicians from using patient assistance programs.

We also suggest the following services:

• www.needymeds.com lists thousands of medications alphabetically (by brand or generic name). Each listing provides complete assistance program information, including the phone number, eligibility criteria, and application form.
  
• GlaxoSmithKline (GSK) patient assistance program. Simply obtain a brief application by calling 1-866-PATIENT (728-4368) or logging onto www.bridgestoaccess.gsk.com. Fill out the form, then call 1-866-PATIENT to activate the attached coupon. Give the patient the coupon and a 60-day prescription for a GSK medication. The patient can fill the prescription at any pharmacy for a $10 co-payment. GSK then mails you 3-month supplies of the medication for 1 year.
  

Abigail Kay, MD
Instructor in psychiatry
Rajnish Mago, MD
Assistant professor of psychiatry
Director, mood disorders program
Thomas Jefferson University, Philadelphia, PA

Dr. Shelley Sellinger’s article “Helping indigent patients obtain medications” (Pearls, Current Psychiatry, April 2005) is helpful for psychiatrists working with patients who lack pharmacy benefits. Not having the information handy or believing the process is too cumbersome may deter some clinicians from using patient assistance programs.

We also suggest the following services:

• www.needymeds.com lists thousands of medications alphabetically (by brand or generic name). Each listing provides complete assistance program information, including the phone number, eligibility criteria, and application form.
  
• GlaxoSmithKline (GSK) patient assistance program. Simply obtain a brief application by calling 1-866-PATIENT (728-4368) or logging onto www.bridgestoaccess.gsk.com. Fill out the form, then call 1-866-PATIENT to activate the attached coupon. Give the patient the coupon and a 60-day prescription for a GSK medication. The patient can fill the prescription at any pharmacy for a $10 co-payment. GSK then mails you 3-month supplies of the medication for 1 year.
  

Abigail Kay, MD
Instructor in psychiatry
Rajnish Mago, MD
Assistant professor of psychiatry
Director, mood disorders program
Thomas Jefferson University, Philadelphia, PA

Dr. Shelley Sellinger’s article “Helping indigent patients obtain medications” (Pearls, Current Psychiatry, April 2005) is helpful for psychiatrists working with patients who lack pharmacy benefits. Not having the information handy or believing the process is too cumbersome may deter some clinicians from using patient assistance programs.

We also suggest the following services:

• www.needymeds.com lists thousands of medications alphabetically (by brand or generic name). Each listing provides complete assistance program information, including the phone number, eligibility criteria, and application form.
  
• GlaxoSmithKline (GSK) patient assistance program. Simply obtain a brief application by calling 1-866-PATIENT (728-4368) or logging onto www.bridgestoaccess.gsk.com. Fill out the form, then call 1-866-PATIENT to activate the attached coupon. Give the patient the coupon and a 60-day prescription for a GSK medication. The patient can fill the prescription at any pharmacy for a $10 co-payment. GSK then mails you 3-month supplies of the medication for 1 year.
  

Abigail Kay, MD
Instructor in psychiatry
Rajnish Mago, MD
Assistant professor of psychiatry
Director, mood disorders program
Thomas Jefferson University, Philadelphia, PA

Is the FDA being overly zealous with its “black box” warnings? The latest advisory—associating atypical antipsychotics with increased mortality among patients with dementia—joins another black box linking these drugs to potentially fatal diabetes. And, as of October, black boxes warn of “clinical worsening” and “suicidality” associated with using SSRI antidepressants in children and adolescents.

An FDA analysis of 5,111 demented patients in 16 trials found about a 1.6-fold increase in mortality among those receiving atypical antipsychotics. According to the Alzheimer’s Association, the risk of death is “real but small;” 1.5% to 2% of the patients receiving antipsychotics died, compared with 1% of those receiving placebo.

Atypical antipsychotics are useful—at times life-saving—for many agitated elderly patients, and this new labeling should not be used as the basis to withhold these drugs from patients who might benefit from them.

Of course, black boxes are not unique to psychotropics. The COX-2 inhibitor arthritis drugs and others recently have joined more than 200 drugs with these warning labels. What leads the FDA to dichotomize drugs into “black-boxed” or “not black-boxed?” And why do black boxes seem to be proliferating?

I think the reason is that the FDA has been criticized for not doing more to prevent adverse drug events and is feeling the pressure. If someone has an adverse event after taking a black-boxed drug, the FDA can now say something like, “I told you so.” This is, as far as I can tell, the same reason for the Department of Homeland Security’s color-coded terrorism threat levels. One could argue that the much-maligned five-level terror rating system (from green to red) is more rational than the FDA’s two-level system, black or not black.

Congress has been debating whether the terrorism threat system is useful or is unnecessarily alarming the public and making us less safe. We should be asking the same questions about the FDA’s black box system.

Is the FDA being overly zealous with its “black box” warnings? The latest advisory—associating atypical antipsychotics with increased mortality among patients with dementia—joins another black box linking these drugs to potentially fatal diabetes. And, as of October, black boxes warn of “clinical worsening” and “suicidality” associated with using SSRI antidepressants in children and adolescents.

An FDA analysis of 5,111 demented patients in 16 trials found about a 1.6-fold increase in mortality among those receiving atypical antipsychotics. According to the Alzheimer’s Association, the risk of death is “real but small;” 1.5% to 2% of the patients receiving antipsychotics died, compared with 1% of those receiving placebo.

Atypical antipsychotics are useful—at times life-saving—for many agitated elderly patients, and this new labeling should not be used as the basis to withhold these drugs from patients who might benefit from them.

Of course, black boxes are not unique to psychotropics. The COX-2 inhibitor arthritis drugs and others recently have joined more than 200 drugs with these warning labels. What leads the FDA to dichotomize drugs into “black-boxed” or “not black-boxed?” And why do black boxes seem to be proliferating?

I think the reason is that the FDA has been criticized for not doing more to prevent adverse drug events and is feeling the pressure. If someone has an adverse event after taking a black-boxed drug, the FDA can now say something like, “I told you so.” This is, as far as I can tell, the same reason for the Department of Homeland Security’s color-coded terrorism threat levels. One could argue that the much-maligned five-level terror rating system (from green to red) is more rational than the FDA’s two-level system, black or not black.

Congress has been debating whether the terrorism threat system is useful or is unnecessarily alarming the public and making us less safe. We should be asking the same questions about the FDA’s black box system.

Is the FDA being overly zealous with its “black box” warnings? The latest advisory—associating atypical antipsychotics with increased mortality among patients with dementia—joins another black box linking these drugs to potentially fatal diabetes. And, as of October, black boxes warn of “clinical worsening” and “suicidality” associated with using SSRI antidepressants in children and adolescents.

An FDA analysis of 5,111 demented patients in 16 trials found about a 1.6-fold increase in mortality among those receiving atypical antipsychotics. According to the Alzheimer’s Association, the risk of death is “real but small;” 1.5% to 2% of the patients receiving antipsychotics died, compared with 1% of those receiving placebo.

Atypical antipsychotics are useful—at times life-saving—for many agitated elderly patients, and this new labeling should not be used as the basis to withhold these drugs from patients who might benefit from them.

Of course, black boxes are not unique to psychotropics. The COX-2 inhibitor arthritis drugs and others recently have joined more than 200 drugs with these warning labels. What leads the FDA to dichotomize drugs into “black-boxed” or “not black-boxed?” And why do black boxes seem to be proliferating?

I think the reason is that the FDA has been criticized for not doing more to prevent adverse drug events and is feeling the pressure. If someone has an adverse event after taking a black-boxed drug, the FDA can now say something like, “I told you so.” This is, as far as I can tell, the same reason for the Department of Homeland Security’s color-coded terrorism threat levels. One could argue that the much-maligned five-level terror rating system (from green to red) is more rational than the FDA’s two-level system, black or not black.

Congress has been debating whether the terrorism threat system is useful or is unnecessarily alarming the public and making us less safe. We should be asking the same questions about the FDA’s black box system.

HISTORY: REPEAT OFFENDER

Mr. V, age 68, was incarcerated for 13 years for two separate pedophilia convictions. During that time, he passed numerous rehabilitative courses. With several years left on his sentence, he was paroled on condition that he undergo a bilateral orchiectomy.

Eight months later, Mr. V complained to his primary care physician that he could not have sex with his girlfriend, even after taking 50 mg of sildenafil, which he had obtained from a friend. He requested testosterone injections to allow him to have intercourse. After consulting an endocrinologist, the physician ordered Mr. V to undergo a psychiatric assessment before receiving testosterone. He was referred to our outpatient clinic.

During our evaluation, Mr. V described both pedophilia incidents. In the first, he had fondled a 14-year-old girl who was a friend of his family. He pled guilty to a charge of inappropriate sexual contact with a minor and was sentenced to 3 years in a state prison for sex offenders.

Less than 2 years after he was paroled, Mr. V said, he fondled his 12-year-old granddaughter. He said his daughter “should have known better” than to leave him home alone with the child. Again he was convicted of illegal sexual relations with a minor and sentenced to 10 years at the state hospital for the criminally insane.

As Mr. V describes his past offenses, we begin feeling tremendously uneasy. Although forthcoming, he blandly denies responsibility for either incident. He acknowledges that society views his actions as wrong, but he never indicates that he believes them to be wrong. At times he tries to normalize his behavior, saying “What man would have acted differently?”

Mr. V is polite and appropriate and promises to abide by our recommendation, yet he sees no reason for us to deny his request and no connection between his criminal record and the nature of his crimes or the terms of his parole. His denial and lack of insight are typical of convicted pedophiles (Box 1).

Box 1

The authors’ observations

Anyone evaluating Mr. V would be inclined to treat or dismiss him, or to suppress his or her feelings to avoid prejudice.

Treat or dismiss. As physicians, we are trained to “First, do no harm.” In this case, however, we must consider who could be harmed by treatment or dismissal.

“First, do no harm” is usually taken to mean “no harm to the patient” but could also be interpreted as “no harm to society.” Even if testosterone treatment did not physically harm Mr. V, activating his sex drive could endanger society by spurring him on to molest another child (Box 2). The treatment could also harm Mr. V by making it easier for him to violate parole.

Although failure to treat Mr. V’s sexual dysfunction would likely pose no harm to society, not assessing him might endanger society by clearing the path toward this treatment.

Box 2

When treating patients such as Mr. V, we must not dismiss our feelings—however uncomfortable or unprofessional they might seem—so that we can manage them appropriately. Don’t be ashamed of your feelings—or at least be aware of your shame.

In such cases, these important steps can minimize the risk of compromising treatment or assessment:

• Be aware of your feelings. Reflecting on countertransference after the session, either alone or with other therapists, can help you recognize your feelings.
  
• Seek peer supervision when evaluating a patient such as Mr. V to help identify potential “blind spots.”
  
• Be aware of your limitations. Hubris is among a therapist’s most serious potential pitfalls. We all have strengths and weaknesses and should be mindful of them.
  

The authors’ observations

We took a passive-neutral stance. Sitting with Mr. V without deciding a course of action gave us time to assess our own reactions and limitations and how they might influence our actions.

CONSULTATION: OTHER OPINIONS

The examining psychiatrist (a psychiatric resident) sought advice from an experienced geriatric psychiatrist, a neuropsychologist, and other residents. We discussed our countertransference toward Mr. V and provided mutual supervision. We then acknowledged that none of us had expertise in treating pedophiles and that treating an unfamiliar mental condition would be unethical.

The authors’ observations

In requesting other opinions, we also weighed these important questions:

Is Mr. V violating parole by requesting testosterone injections and taking (unprescribed) sildenafil? We felt we could not rightfully answer this question, since our expertise in the standard of care for patients such as Mr. V was insufficient and any recommendation would be ill-informed.

Sildenafil use is fairly common among convicted sex offenders, as evidenced by the recent controversy over Medicaid providing the drug to this group (see Related resources).

Assuming the testosterone injections promote intercourse, would they increase Mr. V’s arousal? Hall found that offenders who can voluntarily and completely inhibit sexual arousal are less deviant when not attempting to inhibit arousal than are those who cannot completely inhibit arousal.⁸

Hall, however, urges clinicians to consider variables that influence sexual response before determining how arousal affects an offender’s behavior. With no objective measure of sexual arousal, it is unclear whether increasing Mr. V’s testosterone would heighten it—and his potential threat to society.

The Abel Assessment of Sexual Interest was devised to determine sexual pathology, but evidence suggests this test is clinically unreliable.

Would enhancing Mr. V’s arousal increase his risk of recidivism? Although some studies have found that castration decreases a sex offender’s sexual activity, evidence suggests that sexual responsiveness after castration varies considerably. Heim found that:

• 31% of castrates could still have intercourse
  
• rapists are more sexually active than pedophiles after castration
  
• men ages 46 to 59 experience a greater reduction in sexual behavior than do men age 9
  

What standard of care applies to Mr. V? Treating pedophilia is difficult and poorly understood. Psychotherapy is considered an adjunct to medication or surgery. Surgical interventions are akin to punishment, whereas medications—well-studied and often augmented with psychotherapy—are associated with high recidivism rates.^11,14

Surgery. Orchiectomy is by far the most common surgical intervention. Experimental procedures have targeted stereotaxic ablation of specific parts of the brain, usually the hypothalamus or amygdala, but these techniques have not been adequately studied in humans.¹¹ Even so, testosterone therapy can restore sexual function after castration.¹⁰

Medications. Antiandrogens such as medroxy-progesterone acetate (MPA) inhibit intracellular uptake of androgens (such as testosterone) by blocking their binding to the receptor.¹² MPA is most frequently used in the United States.

Long-acting analogs of gonadotropin-releasing hormone (GnRH), such as leuprolide, nafarelin, goserelin, and triptorelin, have shown efficacy in early studies.¹² These agents down-regulate gonadotroph cells, inducing severe but reversible hypogonadism with few other side effects.

Although decreased libido is a common side effect of selective serotonin reuptake inhibitors (SSRIs), use of these agents to reduce sex drive in convicted pedophiles has not been studied. Because onset of decreased libido with SSRI use is unpredictable, we cannot recommend their use to reduce sex drive in convicted offenders.

Psychotherapy. Power¹⁴ nicely outlines the elements of psychotherapy for pedophilia:

• explanation and education
  
• manipulating the environment
  
• suggestion, including hypnosis and persuasion
  
• superficial analysis
  
• deep-transference analysis
  
• sublimation.
  

• Sentencing laws are often unclear or do not take into account scientific research on pedophilia. For example, psychological testing often is not ordered before a treatment is mandated, even though knowing the patient’s psychological profile and the nature of his predilections are crucial to treatment and prognosis.¹²
  
• Many laws do not suggest an instrument of implementation. For example, most laws that mandate a patient evaluation do not specify whether a licensed psychiatrist, psychologist, or other clinician should evaluate the patient.
  
• Many laws directed against pedophilia are punitive in nature. Mandated treatment—or the informed consent that precedes it—is often inadequate,¹⁰ and physicians can be held liable in either case. However, we could not determine the liability that could result from enhancing a convicted pedophile’s libido.
  

REFERRAL: TREATMENT ADVICE

We referred Mr. V back to his primary care physician and advised the doctor to:

• discuss the testosterone treatment request with physicians who treated Mr. V at the state prison
  
• call our hospital’s attorney to investigate the legal implications of treating Mr. V.
  

Related resources

• Sex offenders get Medicaid-paid Viagra. Associated Press May 22, 2005. http://msnbc.msn.com/id/7946129/.
  
• Conte JR, Wolf S, Smith T. What sexual offenders tell us about prevention strategies. Child Abuse Negl 1989;13:293-301.
  
• U.S. Department of Justice, Bureau of Justice Statistics. Statistics on sex offenders and victims. www.ojp.usdoj.gov/bjs/abstract/saycrle.htm.
  

• Goserelin • Zoladex
  
• Leuprolide • Eligard, others
  
• Medroxyprogesterone acetate • Depo-Provera, others
  
• Nafarelin • Synarel
  
• Sildenafil • Viagra
  
• Triptorelin • Trelstar Depot
  

The authors thank Cynthia Meyer, chief librarian, VA Hospital, Fresno, CA, for her help with researching this article.

Disclosure

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

HISTORY: REPEAT OFFENDER

Mr. V, age 68, was incarcerated for 13 years for two separate pedophilia convictions. During that time, he passed numerous rehabilitative courses. With several years left on his sentence, he was paroled on condition that he undergo a bilateral orchiectomy.

Eight months later, Mr. V complained to his primary care physician that he could not have sex with his girlfriend, even after taking 50 mg of sildenafil, which he had obtained from a friend. He requested testosterone injections to allow him to have intercourse. After consulting an endocrinologist, the physician ordered Mr. V to undergo a psychiatric assessment before receiving testosterone. He was referred to our outpatient clinic.

During our evaluation, Mr. V described both pedophilia incidents. In the first, he had fondled a 14-year-old girl who was a friend of his family. He pled guilty to a charge of inappropriate sexual contact with a minor and was sentenced to 3 years in a state prison for sex offenders.

Less than 2 years after he was paroled, Mr. V said, he fondled his 12-year-old granddaughter. He said his daughter “should have known better” than to leave him home alone with the child. Again he was convicted of illegal sexual relations with a minor and sentenced to 10 years at the state hospital for the criminally insane.

As Mr. V describes his past offenses, we begin feeling tremendously uneasy. Although forthcoming, he blandly denies responsibility for either incident. He acknowledges that society views his actions as wrong, but he never indicates that he believes them to be wrong. At times he tries to normalize his behavior, saying “What man would have acted differently?”

Mr. V is polite and appropriate and promises to abide by our recommendation, yet he sees no reason for us to deny his request and no connection between his criminal record and the nature of his crimes or the terms of his parole. His denial and lack of insight are typical of convicted pedophiles (Box 1).

Box 1

The authors’ observations

Anyone evaluating Mr. V would be inclined to treat or dismiss him, or to suppress his or her feelings to avoid prejudice.

Treat or dismiss. As physicians, we are trained to “First, do no harm.” In this case, however, we must consider who could be harmed by treatment or dismissal.

“First, do no harm” is usually taken to mean “no harm to the patient” but could also be interpreted as “no harm to society.” Even if testosterone treatment did not physically harm Mr. V, activating his sex drive could endanger society by spurring him on to molest another child (Box 2). The treatment could also harm Mr. V by making it easier for him to violate parole.

Although failure to treat Mr. V’s sexual dysfunction would likely pose no harm to society, not assessing him might endanger society by clearing the path toward this treatment.

Box 2

When treating patients such as Mr. V, we must not dismiss our feelings—however uncomfortable or unprofessional they might seem—so that we can manage them appropriately. Don’t be ashamed of your feelings—or at least be aware of your shame.

In such cases, these important steps can minimize the risk of compromising treatment or assessment:

• Be aware of your feelings. Reflecting on countertransference after the session, either alone or with other therapists, can help you recognize your feelings.
  
• Seek peer supervision when evaluating a patient such as Mr. V to help identify potential “blind spots.”
  
• Be aware of your limitations. Hubris is among a therapist’s most serious potential pitfalls. We all have strengths and weaknesses and should be mindful of them.
  

The authors’ observations

We took a passive-neutral stance. Sitting with Mr. V without deciding a course of action gave us time to assess our own reactions and limitations and how they might influence our actions.

CONSULTATION: OTHER OPINIONS

The examining psychiatrist (a psychiatric resident) sought advice from an experienced geriatric psychiatrist, a neuropsychologist, and other residents. We discussed our countertransference toward Mr. V and provided mutual supervision. We then acknowledged that none of us had expertise in treating pedophiles and that treating an unfamiliar mental condition would be unethical.

The authors’ observations

In requesting other opinions, we also weighed these important questions:

Is Mr. V violating parole by requesting testosterone injections and taking (unprescribed) sildenafil? We felt we could not rightfully answer this question, since our expertise in the standard of care for patients such as Mr. V was insufficient and any recommendation would be ill-informed.

Sildenafil use is fairly common among convicted sex offenders, as evidenced by the recent controversy over Medicaid providing the drug to this group (see Related resources).

Assuming the testosterone injections promote intercourse, would they increase Mr. V’s arousal? Hall found that offenders who can voluntarily and completely inhibit sexual arousal are less deviant when not attempting to inhibit arousal than are those who cannot completely inhibit arousal.⁸

Hall, however, urges clinicians to consider variables that influence sexual response before determining how arousal affects an offender’s behavior. With no objective measure of sexual arousal, it is unclear whether increasing Mr. V’s testosterone would heighten it—and his potential threat to society.

The Abel Assessment of Sexual Interest was devised to determine sexual pathology, but evidence suggests this test is clinically unreliable.

Would enhancing Mr. V’s arousal increase his risk of recidivism? Although some studies have found that castration decreases a sex offender’s sexual activity, evidence suggests that sexual responsiveness after castration varies considerably. Heim found that:

• 31% of castrates could still have intercourse
  
• rapists are more sexually active than pedophiles after castration
  
• men ages 46 to 59 experience a greater reduction in sexual behavior than do men age 9
  

What standard of care applies to Mr. V? Treating pedophilia is difficult and poorly understood. Psychotherapy is considered an adjunct to medication or surgery. Surgical interventions are akin to punishment, whereas medications—well-studied and often augmented with psychotherapy—are associated with high recidivism rates.^11,14

Surgery. Orchiectomy is by far the most common surgical intervention. Experimental procedures have targeted stereotaxic ablation of specific parts of the brain, usually the hypothalamus or amygdala, but these techniques have not been adequately studied in humans.¹¹ Even so, testosterone therapy can restore sexual function after castration.¹⁰

Medications. Antiandrogens such as medroxy-progesterone acetate (MPA) inhibit intracellular uptake of androgens (such as testosterone) by blocking their binding to the receptor.¹² MPA is most frequently used in the United States.

Long-acting analogs of gonadotropin-releasing hormone (GnRH), such as leuprolide, nafarelin, goserelin, and triptorelin, have shown efficacy in early studies.¹² These agents down-regulate gonadotroph cells, inducing severe but reversible hypogonadism with few other side effects.

Although decreased libido is a common side effect of selective serotonin reuptake inhibitors (SSRIs), use of these agents to reduce sex drive in convicted pedophiles has not been studied. Because onset of decreased libido with SSRI use is unpredictable, we cannot recommend their use to reduce sex drive in convicted offenders.

Psychotherapy. Power¹⁴ nicely outlines the elements of psychotherapy for pedophilia:

• explanation and education
  
• manipulating the environment
  
• suggestion, including hypnosis and persuasion
  
• superficial analysis
  
• deep-transference analysis
  
• sublimation.
  

• Sentencing laws are often unclear or do not take into account scientific research on pedophilia. For example, psychological testing often is not ordered before a treatment is mandated, even though knowing the patient’s psychological profile and the nature of his predilections are crucial to treatment and prognosis.¹²
  
• Many laws do not suggest an instrument of implementation. For example, most laws that mandate a patient evaluation do not specify whether a licensed psychiatrist, psychologist, or other clinician should evaluate the patient.
  
• Many laws directed against pedophilia are punitive in nature. Mandated treatment—or the informed consent that precedes it—is often inadequate,¹⁰ and physicians can be held liable in either case. However, we could not determine the liability that could result from enhancing a convicted pedophile’s libido.
  

REFERRAL: TREATMENT ADVICE

We referred Mr. V back to his primary care physician and advised the doctor to:

• discuss the testosterone treatment request with physicians who treated Mr. V at the state prison
  
• call our hospital’s attorney to investigate the legal implications of treating Mr. V.
  

Related resources

• Sex offenders get Medicaid-paid Viagra. Associated Press May 22, 2005. http://msnbc.msn.com/id/7946129/.
  
• Conte JR, Wolf S, Smith T. What sexual offenders tell us about prevention strategies. Child Abuse Negl 1989;13:293-301.
  
• U.S. Department of Justice, Bureau of Justice Statistics. Statistics on sex offenders and victims. www.ojp.usdoj.gov/bjs/abstract/saycrle.htm.
  

• Goserelin • Zoladex
  
• Leuprolide • Eligard, others
  
• Medroxyprogesterone acetate • Depo-Provera, others
  
• Nafarelin • Synarel
  
• Sildenafil • Viagra
  
• Triptorelin • Trelstar Depot
  

The authors thank Cynthia Meyer, chief librarian, VA Hospital, Fresno, CA, for her help with researching this article.

Disclosure

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

HISTORY: REPEAT OFFENDER

Mr. V, age 68, was incarcerated for 13 years for two separate pedophilia convictions. During that time, he passed numerous rehabilitative courses. With several years left on his sentence, he was paroled on condition that he undergo a bilateral orchiectomy.

Eight months later, Mr. V complained to his primary care physician that he could not have sex with his girlfriend, even after taking 50 mg of sildenafil, which he had obtained from a friend. He requested testosterone injections to allow him to have intercourse. After consulting an endocrinologist, the physician ordered Mr. V to undergo a psychiatric assessment before receiving testosterone. He was referred to our outpatient clinic.

During our evaluation, Mr. V described both pedophilia incidents. In the first, he had fondled a 14-year-old girl who was a friend of his family. He pled guilty to a charge of inappropriate sexual contact with a minor and was sentenced to 3 years in a state prison for sex offenders.

Less than 2 years after he was paroled, Mr. V said, he fondled his 12-year-old granddaughter. He said his daughter “should have known better” than to leave him home alone with the child. Again he was convicted of illegal sexual relations with a minor and sentenced to 10 years at the state hospital for the criminally insane.

As Mr. V describes his past offenses, we begin feeling tremendously uneasy. Although forthcoming, he blandly denies responsibility for either incident. He acknowledges that society views his actions as wrong, but he never indicates that he believes them to be wrong. At times he tries to normalize his behavior, saying “What man would have acted differently?”

Mr. V is polite and appropriate and promises to abide by our recommendation, yet he sees no reason for us to deny his request and no connection between his criminal record and the nature of his crimes or the terms of his parole. His denial and lack of insight are typical of convicted pedophiles (Box 1).

Box 1

The authors’ observations

Anyone evaluating Mr. V would be inclined to treat or dismiss him, or to suppress his or her feelings to avoid prejudice.

Treat or dismiss. As physicians, we are trained to “First, do no harm.” In this case, however, we must consider who could be harmed by treatment or dismissal.

“First, do no harm” is usually taken to mean “no harm to the patient” but could also be interpreted as “no harm to society.” Even if testosterone treatment did not physically harm Mr. V, activating his sex drive could endanger society by spurring him on to molest another child (Box 2). The treatment could also harm Mr. V by making it easier for him to violate parole.

Although failure to treat Mr. V’s sexual dysfunction would likely pose no harm to society, not assessing him might endanger society by clearing the path toward this treatment.

Box 2

When treating patients such as Mr. V, we must not dismiss our feelings—however uncomfortable or unprofessional they might seem—so that we can manage them appropriately. Don’t be ashamed of your feelings—or at least be aware of your shame.

In such cases, these important steps can minimize the risk of compromising treatment or assessment:

• Be aware of your feelings. Reflecting on countertransference after the session, either alone or with other therapists, can help you recognize your feelings.
  
• Seek peer supervision when evaluating a patient such as Mr. V to help identify potential “blind spots.”
  
• Be aware of your limitations. Hubris is among a therapist’s most serious potential pitfalls. We all have strengths and weaknesses and should be mindful of them.
  

The authors’ observations

We took a passive-neutral stance. Sitting with Mr. V without deciding a course of action gave us time to assess our own reactions and limitations and how they might influence our actions.

CONSULTATION: OTHER OPINIONS

The examining psychiatrist (a psychiatric resident) sought advice from an experienced geriatric psychiatrist, a neuropsychologist, and other residents. We discussed our countertransference toward Mr. V and provided mutual supervision. We then acknowledged that none of us had expertise in treating pedophiles and that treating an unfamiliar mental condition would be unethical.

The authors’ observations

In requesting other opinions, we also weighed these important questions:

Is Mr. V violating parole by requesting testosterone injections and taking (unprescribed) sildenafil? We felt we could not rightfully answer this question, since our expertise in the standard of care for patients such as Mr. V was insufficient and any recommendation would be ill-informed.

Sildenafil use is fairly common among convicted sex offenders, as evidenced by the recent controversy over Medicaid providing the drug to this group (see Related resources).

Assuming the testosterone injections promote intercourse, would they increase Mr. V’s arousal? Hall found that offenders who can voluntarily and completely inhibit sexual arousal are less deviant when not attempting to inhibit arousal than are those who cannot completely inhibit arousal.⁸

Hall, however, urges clinicians to consider variables that influence sexual response before determining how arousal affects an offender’s behavior. With no objective measure of sexual arousal, it is unclear whether increasing Mr. V’s testosterone would heighten it—and his potential threat to society.

The Abel Assessment of Sexual Interest was devised to determine sexual pathology, but evidence suggests this test is clinically unreliable.

Would enhancing Mr. V’s arousal increase his risk of recidivism? Although some studies have found that castration decreases a sex offender’s sexual activity, evidence suggests that sexual responsiveness after castration varies considerably. Heim found that:

• 31% of castrates could still have intercourse
  
• rapists are more sexually active than pedophiles after castration
  
• men ages 46 to 59 experience a greater reduction in sexual behavior than do men age 9
  

What standard of care applies to Mr. V? Treating pedophilia is difficult and poorly understood. Psychotherapy is considered an adjunct to medication or surgery. Surgical interventions are akin to punishment, whereas medications—well-studied and often augmented with psychotherapy—are associated with high recidivism rates.^11,14

Surgery. Orchiectomy is by far the most common surgical intervention. Experimental procedures have targeted stereotaxic ablation of specific parts of the brain, usually the hypothalamus or amygdala, but these techniques have not been adequately studied in humans.¹¹ Even so, testosterone therapy can restore sexual function after castration.¹⁰

Medications. Antiandrogens such as medroxy-progesterone acetate (MPA) inhibit intracellular uptake of androgens (such as testosterone) by blocking their binding to the receptor.¹² MPA is most frequently used in the United States.

Long-acting analogs of gonadotropin-releasing hormone (GnRH), such as leuprolide, nafarelin, goserelin, and triptorelin, have shown efficacy in early studies.¹² These agents down-regulate gonadotroph cells, inducing severe but reversible hypogonadism with few other side effects.

Although decreased libido is a common side effect of selective serotonin reuptake inhibitors (SSRIs), use of these agents to reduce sex drive in convicted pedophiles has not been studied. Because onset of decreased libido with SSRI use is unpredictable, we cannot recommend their use to reduce sex drive in convicted offenders.

Psychotherapy. Power¹⁴ nicely outlines the elements of psychotherapy for pedophilia:

• explanation and education
  
• manipulating the environment
  
• suggestion, including hypnosis and persuasion
  
• superficial analysis
  
• deep-transference analysis
  
• sublimation.
  

• Sentencing laws are often unclear or do not take into account scientific research on pedophilia. For example, psychological testing often is not ordered before a treatment is mandated, even though knowing the patient’s psychological profile and the nature of his predilections are crucial to treatment and prognosis.¹²
  
• Many laws do not suggest an instrument of implementation. For example, most laws that mandate a patient evaluation do not specify whether a licensed psychiatrist, psychologist, or other clinician should evaluate the patient.
  
• Many laws directed against pedophilia are punitive in nature. Mandated treatment—or the informed consent that precedes it—is often inadequate,¹⁰ and physicians can be held liable in either case. However, we could not determine the liability that could result from enhancing a convicted pedophile’s libido.
  

REFERRAL: TREATMENT ADVICE

We referred Mr. V back to his primary care physician and advised the doctor to:

• discuss the testosterone treatment request with physicians who treated Mr. V at the state prison
  
• call our hospital’s attorney to investigate the legal implications of treating Mr. V.
  

Related resources

• Sex offenders get Medicaid-paid Viagra. Associated Press May 22, 2005. http://msnbc.msn.com/id/7946129/.
  
• Conte JR, Wolf S, Smith T. What sexual offenders tell us about prevention strategies. Child Abuse Negl 1989;13:293-301.
  
• U.S. Department of Justice, Bureau of Justice Statistics. Statistics on sex offenders and victims. www.ojp.usdoj.gov/bjs/abstract/saycrle.htm.
  

• Goserelin • Zoladex
  
• Leuprolide • Eligard, others
  
• Medroxyprogesterone acetate • Depo-Provera, others
  
• Nafarelin • Synarel
  
• Sildenafil • Viagra
  
• Triptorelin • Trelstar Depot
  

The authors thank Cynthia Meyer, chief librarian, VA Hospital, Fresno, CA, for her help with researching this article.

Disclosure

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

Aripiprazole, the first FDA-approved partial dopamine agonist, causes few side effects when used to treat schizophrenia or acute bipolar mania. This relatively safe profile in approved uses has led clinicians to try aripiprazole for off-label uses as well, though evidence of the drug’s efficacy and safety in other psychiatric conditions is limited (Box 1).^1-7 Because this practice may involve unknown risks, this article:

• reviews aripiprazole’s role in correcting dopaminergic dysfunction in patients with schizophrenia
• cites adverse effects reported with aripiprazole use and discusses concerns about its off-label use.

Box 1

DOPAMINE AND SCHIZOPHRENIA

Dopamine neurons arise from two major nuclei in the mesencephalon (midbrain): the substantia nigra and ventral tegmental area (VTA). Neurons from the substantia nigra extend to the basal ganglia via the mesostriatal (nigrostriatal) pathway, which influences extrapyramidal motor function. The VTA sends dopaminergic neurons through mesolimbic and mesocortical pathways.

The basic limbic system includes the cingulate and orbitofrontal gyri, hippocampus, hypothalamus, thalamus, amygdala, medial temporal cortex, and the periaqueductal gray. This system controls emotion, episodic memory, pain, and primitive behaviors such as eating, fighting, sexual desire, and grooming.⁸ The limbic system is surrounded by cortex, where higher-order sensory, cognitive, and motor processes occur. The VTA links limbic and cortical functions via dopamine.

The tuberoinfundibular pathway, another clinically important dopaminergic route, projects from the hypothalamus to the anterior pituitary gland and regulates prolactin secretion.

Functional dopamine neurotransmission abnormalities in schizophrenia are generally characterized by region, with:

• excessive mesolimbic pathway activity resulting in positive symptoms such as delusions and hallucinations
• mesocortical projection deficits resulting in cognitive and negative symptoms such as impaired memory and attention, emotional blunting, alogia, avolition, and anhedonia.

Dopamine function abnormalities in schizophrenia occur in:

• projections from the substantia nigra to the caudate and putamen in the basal ganglia
• mesolimbic connections to the anterior cingulate, hippocampus, and parahippocampus
• mesocortical projections to the prefrontal cortex.

These dysfunctions contribute to abnormal motor function, perception, attention, memory, volition, emotion, and executive function.⁹

WHY ARIPIPRAZOLE WAS CREATED

Differences in regional dopamine function and observations of dopamine agonists’ therapeutic effects in schizophrenia¹⁰ led to development of partial dopamine agonists such as aripiprazole (Box 2).^11,12

Aripiprazole and the investigational agent bifeprunox have complex pharmacologic actions involving numerous neurotransmitters—dopamine, serotonin, and histamine—but are believed to be principally partial agonists at pre- and postsynaptic dopamine receptors. Specifically, aripiprazole decreases hyperdopaminergic states while preserving dopamine function by partial agonism and decreased stimulation of presynaptic regulatory autoreceptors.⁵

The FDA approved aripiprazole for treating schizophrenia in 2002 and acute bipolar mania in 2004. A dihydroquinolone unrelated to other antipsychotics, it has an active partial agonist metabolite (dehydro-aripiprazole), high affinity for D2 receptors (Figure 1), and partial agonism at dopamine and serotonin receptors.¹³

Phase III trials are in progress for bifeprunox, a partial dopamine agonist/antagonist and serotonin receptor agonist being investigated for schizophrenia. An FDA decision on its approvability is expected in 2007.

Aripiprazole has approximately 30% intrinsic dopaminergic activity, estimated from studies showing a low incidence of extrapyramidal symptoms (EPS) with dosages up to 30 mg and PET studies showing a therapeutic range of postsynaptic D2 receptor occupancy of 80% to 95%.¹⁴ This small intrinsic activity limits excessive stimulation and dopamine receptor blockade.¹¹ It also limits down-regulation of regulatory dopamine autoreceptors and preserves dopaminergic function in pre- and postsynaptic neurons.

The therapeutic window for dopamine receptor agonists (DA) and serotonin-dopamine receptor agonists (SDA) used in schizophrenia is 60% to 80% D2 receptor occupancy in mesostriatal neurons. D2 receptor occupancy and antagonism >80% significantly increases risk of EPS.¹⁵ Excessive dosing of high-potency antipsychotics with strong postsynaptic dopamine receptor affinity carries the highest risk of hypodopaminergic side effects, such as cognitive impairment, worsening of negative symptoms, akathisia, Parkinsonism, and hyperprolactinemia.

Aripiprazole’s intrinsic activity allows for higher D2 receptor occupancy with fewer side effects associated with full dopamine receptor antagonism. Clinical implications of this profile are unknown. Dopamine’s role in schizophrenia’s pathophysiology is inferred from knowledge that all effective antipsychotics offer some postsynaptic D2 receptor blockade.

Box 2

FigureAntipsychotics’ D2 receptor binding affinities

SIDE EFFECTS

Evidence shows fewer side effects with aripiprazole when used to treat schizophrenia and schizoaffective disorder compared with DAs such as haloperidol and SDAs such as risperidone.^1,2,4

Dosage-dependent somnolence occurs with aripiprazole; the most common side effects include headache, agitation, anxiety, and insomnia (24.5%, 34.6%, 24%, and 18.6%, respectively).² continued on page 60 A 10-week, placebo-controlled study using aripiprazole, 2 to 15 mg/d, to treat psychosis in Alzheimer’s dementia showed significantly increased risk of somnolence, accidental injury, and bronchitis (likely caused by aspiration).¹⁶

In placebo-controlled trials, aripiprazole, 2 to 30 mg/d, did not increase risk of cardiac, lipid, or prolactin-related side effects² but showed increased risk of:

• tremor when used at 15 mg/d for up to 26 weeks in chronic schizophrenia, (9% incidence vs 1% with placebo)¹⁷
• akathisia when used at mean dosages of 27.9 mg/d to treat acute bipolar mania (11% incidence vs 2%with placebo).³ Aripiprazole also increased akathisia incidence in normal subjects.¹⁸

Risk of tardive dyskinesia or hyperglycemia-related adverse events with aripiprazole are unknown. Studies report weight gain of <1 kg (<2.2 lbs) in patients taking aripiprazole, 2 to 30 mg/d. One study found that patients switched from DA and SDA antipsychotics to aripiprazole, 30 mg/d, lost on average 1.5 kg (3.2 lbs) across 8weeks.¹⁹

Determining neuroleptic malignant syndrome risk with aripiprazole is difficult; two cases were reported in the premarketing sample.¹⁶ One animal study showed diminished catalepsy with chronic aripiprazole use, in contrast to persistent catalepsy with haloperidol.²⁰

A Medline search for aripiprazole in February 2005 found several reports of treatment-emergent side effects, including:

• 3 reports of worsening agitation or psychosis^21-23
• 2 reports of EPS^24,25
• 1 report of excessive somnolence in a child.²⁶

Adverse effects are probably underrepresented. Clinical deterioration and adverse effects were reported after starting, switching to, or combining aripiprazole with other antipsychotics or serotonergic agents (trazodone, sertraline, or venlafaxine).^27,28

Related resources

• Lieberman, J. Aripiprazole. In: Schatzberg, A, Nemeroff, C (eds.) Textbook of Psychopharmacology. Washington DC: American Psychiatric Publishing, 2004:487-494.
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/foi/nda/2002/21-436_Abilify.htm
• Medline Plus Drug Information. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a603012.html

Drug brand names

• Aripiprazole •Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Risperidone • Risperdal
• Trazodone • Desyrel
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

This author is supported by grant 2R25MH060490-06 from the National Institute of Mental Health.

Aripiprazole, the first FDA-approved partial dopamine agonist, causes few side effects when used to treat schizophrenia or acute bipolar mania. This relatively safe profile in approved uses has led clinicians to try aripiprazole for off-label uses as well, though evidence of the drug’s efficacy and safety in other psychiatric conditions is limited (Box 1).^1-7 Because this practice may involve unknown risks, this article:

• reviews aripiprazole’s role in correcting dopaminergic dysfunction in patients with schizophrenia
• cites adverse effects reported with aripiprazole use and discusses concerns about its off-label use.

Box 1

DOPAMINE AND SCHIZOPHRENIA

Dopamine neurons arise from two major nuclei in the mesencephalon (midbrain): the substantia nigra and ventral tegmental area (VTA). Neurons from the substantia nigra extend to the basal ganglia via the mesostriatal (nigrostriatal) pathway, which influences extrapyramidal motor function. The VTA sends dopaminergic neurons through mesolimbic and mesocortical pathways.

The basic limbic system includes the cingulate and orbitofrontal gyri, hippocampus, hypothalamus, thalamus, amygdala, medial temporal cortex, and the periaqueductal gray. This system controls emotion, episodic memory, pain, and primitive behaviors such as eating, fighting, sexual desire, and grooming.⁸ The limbic system is surrounded by cortex, where higher-order sensory, cognitive, and motor processes occur. The VTA links limbic and cortical functions via dopamine.

The tuberoinfundibular pathway, another clinically important dopaminergic route, projects from the hypothalamus to the anterior pituitary gland and regulates prolactin secretion.

Functional dopamine neurotransmission abnormalities in schizophrenia are generally characterized by region, with:

• excessive mesolimbic pathway activity resulting in positive symptoms such as delusions and hallucinations
• mesocortical projection deficits resulting in cognitive and negative symptoms such as impaired memory and attention, emotional blunting, alogia, avolition, and anhedonia.

Dopamine function abnormalities in schizophrenia occur in:

• projections from the substantia nigra to the caudate and putamen in the basal ganglia
• mesolimbic connections to the anterior cingulate, hippocampus, and parahippocampus
• mesocortical projections to the prefrontal cortex.

These dysfunctions contribute to abnormal motor function, perception, attention, memory, volition, emotion, and executive function.⁹

WHY ARIPIPRAZOLE WAS CREATED

Differences in regional dopamine function and observations of dopamine agonists’ therapeutic effects in schizophrenia¹⁰ led to development of partial dopamine agonists such as aripiprazole (Box 2).^11,12

Aripiprazole and the investigational agent bifeprunox have complex pharmacologic actions involving numerous neurotransmitters—dopamine, serotonin, and histamine—but are believed to be principally partial agonists at pre- and postsynaptic dopamine receptors. Specifically, aripiprazole decreases hyperdopaminergic states while preserving dopamine function by partial agonism and decreased stimulation of presynaptic regulatory autoreceptors.⁵

The FDA approved aripiprazole for treating schizophrenia in 2002 and acute bipolar mania in 2004. A dihydroquinolone unrelated to other antipsychotics, it has an active partial agonist metabolite (dehydro-aripiprazole), high affinity for D2 receptors (Figure 1), and partial agonism at dopamine and serotonin receptors.¹³

Phase III trials are in progress for bifeprunox, a partial dopamine agonist/antagonist and serotonin receptor agonist being investigated for schizophrenia. An FDA decision on its approvability is expected in 2007.

Aripiprazole has approximately 30% intrinsic dopaminergic activity, estimated from studies showing a low incidence of extrapyramidal symptoms (EPS) with dosages up to 30 mg and PET studies showing a therapeutic range of postsynaptic D2 receptor occupancy of 80% to 95%.¹⁴ This small intrinsic activity limits excessive stimulation and dopamine receptor blockade.¹¹ It also limits down-regulation of regulatory dopamine autoreceptors and preserves dopaminergic function in pre- and postsynaptic neurons.

The therapeutic window for dopamine receptor agonists (DA) and serotonin-dopamine receptor agonists (SDA) used in schizophrenia is 60% to 80% D2 receptor occupancy in mesostriatal neurons. D2 receptor occupancy and antagonism >80% significantly increases risk of EPS.¹⁵ Excessive dosing of high-potency antipsychotics with strong postsynaptic dopamine receptor affinity carries the highest risk of hypodopaminergic side effects, such as cognitive impairment, worsening of negative symptoms, akathisia, Parkinsonism, and hyperprolactinemia.

Aripiprazole’s intrinsic activity allows for higher D2 receptor occupancy with fewer side effects associated with full dopamine receptor antagonism. Clinical implications of this profile are unknown. Dopamine’s role in schizophrenia’s pathophysiology is inferred from knowledge that all effective antipsychotics offer some postsynaptic D2 receptor blockade.

Box 2

FigureAntipsychotics’ D2 receptor binding affinities

SIDE EFFECTS

Evidence shows fewer side effects with aripiprazole when used to treat schizophrenia and schizoaffective disorder compared with DAs such as haloperidol and SDAs such as risperidone.^1,2,4

Dosage-dependent somnolence occurs with aripiprazole; the most common side effects include headache, agitation, anxiety, and insomnia (24.5%, 34.6%, 24%, and 18.6%, respectively).² continued on page 60 A 10-week, placebo-controlled study using aripiprazole, 2 to 15 mg/d, to treat psychosis in Alzheimer’s dementia showed significantly increased risk of somnolence, accidental injury, and bronchitis (likely caused by aspiration).¹⁶

In placebo-controlled trials, aripiprazole, 2 to 30 mg/d, did not increase risk of cardiac, lipid, or prolactin-related side effects² but showed increased risk of:

• tremor when used at 15 mg/d for up to 26 weeks in chronic schizophrenia, (9% incidence vs 1% with placebo)¹⁷
• akathisia when used at mean dosages of 27.9 mg/d to treat acute bipolar mania (11% incidence vs 2%with placebo).³ Aripiprazole also increased akathisia incidence in normal subjects.¹⁸

Risk of tardive dyskinesia or hyperglycemia-related adverse events with aripiprazole are unknown. Studies report weight gain of <1 kg (<2.2 lbs) in patients taking aripiprazole, 2 to 30 mg/d. One study found that patients switched from DA and SDA antipsychotics to aripiprazole, 30 mg/d, lost on average 1.5 kg (3.2 lbs) across 8weeks.¹⁹

Determining neuroleptic malignant syndrome risk with aripiprazole is difficult; two cases were reported in the premarketing sample.¹⁶ One animal study showed diminished catalepsy with chronic aripiprazole use, in contrast to persistent catalepsy with haloperidol.²⁰

A Medline search for aripiprazole in February 2005 found several reports of treatment-emergent side effects, including:

• 3 reports of worsening agitation or psychosis^21-23
• 2 reports of EPS^24,25
• 1 report of excessive somnolence in a child.²⁶

Adverse effects are probably underrepresented. Clinical deterioration and adverse effects were reported after starting, switching to, or combining aripiprazole with other antipsychotics or serotonergic agents (trazodone, sertraline, or venlafaxine).^27,28

Related resources

• Lieberman, J. Aripiprazole. In: Schatzberg, A, Nemeroff, C (eds.) Textbook of Psychopharmacology. Washington DC: American Psychiatric Publishing, 2004:487-494.
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/foi/nda/2002/21-436_Abilify.htm
• Medline Plus Drug Information. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a603012.html

Drug brand names

• Aripiprazole •Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Risperidone • Risperdal
• Trazodone • Desyrel
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

This author is supported by grant 2R25MH060490-06 from the National Institute of Mental Health.

Aripiprazole, the first FDA-approved partial dopamine agonist, causes few side effects when used to treat schizophrenia or acute bipolar mania. This relatively safe profile in approved uses has led clinicians to try aripiprazole for off-label uses as well, though evidence of the drug’s efficacy and safety in other psychiatric conditions is limited (Box 1).^1-7 Because this practice may involve unknown risks, this article:

• reviews aripiprazole’s role in correcting dopaminergic dysfunction in patients with schizophrenia
• cites adverse effects reported with aripiprazole use and discusses concerns about its off-label use.

Box 1

DOPAMINE AND SCHIZOPHRENIA

Dopamine neurons arise from two major nuclei in the mesencephalon (midbrain): the substantia nigra and ventral tegmental area (VTA). Neurons from the substantia nigra extend to the basal ganglia via the mesostriatal (nigrostriatal) pathway, which influences extrapyramidal motor function. The VTA sends dopaminergic neurons through mesolimbic and mesocortical pathways.

The basic limbic system includes the cingulate and orbitofrontal gyri, hippocampus, hypothalamus, thalamus, amygdala, medial temporal cortex, and the periaqueductal gray. This system controls emotion, episodic memory, pain, and primitive behaviors such as eating, fighting, sexual desire, and grooming.⁸ The limbic system is surrounded by cortex, where higher-order sensory, cognitive, and motor processes occur. The VTA links limbic and cortical functions via dopamine.

The tuberoinfundibular pathway, another clinically important dopaminergic route, projects from the hypothalamus to the anterior pituitary gland and regulates prolactin secretion.

Functional dopamine neurotransmission abnormalities in schizophrenia are generally characterized by region, with:

• excessive mesolimbic pathway activity resulting in positive symptoms such as delusions and hallucinations
• mesocortical projection deficits resulting in cognitive and negative symptoms such as impaired memory and attention, emotional blunting, alogia, avolition, and anhedonia.

Dopamine function abnormalities in schizophrenia occur in:

• projections from the substantia nigra to the caudate and putamen in the basal ganglia
• mesolimbic connections to the anterior cingulate, hippocampus, and parahippocampus
• mesocortical projections to the prefrontal cortex.

These dysfunctions contribute to abnormal motor function, perception, attention, memory, volition, emotion, and executive function.⁹

WHY ARIPIPRAZOLE WAS CREATED

Differences in regional dopamine function and observations of dopamine agonists’ therapeutic effects in schizophrenia¹⁰ led to development of partial dopamine agonists such as aripiprazole (Box 2).^11,12

Aripiprazole and the investigational agent bifeprunox have complex pharmacologic actions involving numerous neurotransmitters—dopamine, serotonin, and histamine—but are believed to be principally partial agonists at pre- and postsynaptic dopamine receptors. Specifically, aripiprazole decreases hyperdopaminergic states while preserving dopamine function by partial agonism and decreased stimulation of presynaptic regulatory autoreceptors.⁵

The FDA approved aripiprazole for treating schizophrenia in 2002 and acute bipolar mania in 2004. A dihydroquinolone unrelated to other antipsychotics, it has an active partial agonist metabolite (dehydro-aripiprazole), high affinity for D2 receptors (Figure 1), and partial agonism at dopamine and serotonin receptors.¹³

Phase III trials are in progress for bifeprunox, a partial dopamine agonist/antagonist and serotonin receptor agonist being investigated for schizophrenia. An FDA decision on its approvability is expected in 2007.

Aripiprazole has approximately 30% intrinsic dopaminergic activity, estimated from studies showing a low incidence of extrapyramidal symptoms (EPS) with dosages up to 30 mg and PET studies showing a therapeutic range of postsynaptic D2 receptor occupancy of 80% to 95%.¹⁴ This small intrinsic activity limits excessive stimulation and dopamine receptor blockade.¹¹ It also limits down-regulation of regulatory dopamine autoreceptors and preserves dopaminergic function in pre- and postsynaptic neurons.

The therapeutic window for dopamine receptor agonists (DA) and serotonin-dopamine receptor agonists (SDA) used in schizophrenia is 60% to 80% D2 receptor occupancy in mesostriatal neurons. D2 receptor occupancy and antagonism >80% significantly increases risk of EPS.¹⁵ Excessive dosing of high-potency antipsychotics with strong postsynaptic dopamine receptor affinity carries the highest risk of hypodopaminergic side effects, such as cognitive impairment, worsening of negative symptoms, akathisia, Parkinsonism, and hyperprolactinemia.

Aripiprazole’s intrinsic activity allows for higher D2 receptor occupancy with fewer side effects associated with full dopamine receptor antagonism. Clinical implications of this profile are unknown. Dopamine’s role in schizophrenia’s pathophysiology is inferred from knowledge that all effective antipsychotics offer some postsynaptic D2 receptor blockade.

Box 2

FigureAntipsychotics’ D2 receptor binding affinities

SIDE EFFECTS

Evidence shows fewer side effects with aripiprazole when used to treat schizophrenia and schizoaffective disorder compared with DAs such as haloperidol and SDAs such as risperidone.^1,2,4

Dosage-dependent somnolence occurs with aripiprazole; the most common side effects include headache, agitation, anxiety, and insomnia (24.5%, 34.6%, 24%, and 18.6%, respectively).² continued on page 60 A 10-week, placebo-controlled study using aripiprazole, 2 to 15 mg/d, to treat psychosis in Alzheimer’s dementia showed significantly increased risk of somnolence, accidental injury, and bronchitis (likely caused by aspiration).¹⁶

In placebo-controlled trials, aripiprazole, 2 to 30 mg/d, did not increase risk of cardiac, lipid, or prolactin-related side effects² but showed increased risk of:

• tremor when used at 15 mg/d for up to 26 weeks in chronic schizophrenia, (9% incidence vs 1% with placebo)¹⁷
• akathisia when used at mean dosages of 27.9 mg/d to treat acute bipolar mania (11% incidence vs 2%with placebo).³ Aripiprazole also increased akathisia incidence in normal subjects.¹⁸

Risk of tardive dyskinesia or hyperglycemia-related adverse events with aripiprazole are unknown. Studies report weight gain of <1 kg (<2.2 lbs) in patients taking aripiprazole, 2 to 30 mg/d. One study found that patients switched from DA and SDA antipsychotics to aripiprazole, 30 mg/d, lost on average 1.5 kg (3.2 lbs) across 8weeks.¹⁹

Determining neuroleptic malignant syndrome risk with aripiprazole is difficult; two cases were reported in the premarketing sample.¹⁶ One animal study showed diminished catalepsy with chronic aripiprazole use, in contrast to persistent catalepsy with haloperidol.²⁰

A Medline search for aripiprazole in February 2005 found several reports of treatment-emergent side effects, including:

• 3 reports of worsening agitation or psychosis^21-23
• 2 reports of EPS^24,25
• 1 report of excessive somnolence in a child.²⁶

Adverse effects are probably underrepresented. Clinical deterioration and adverse effects were reported after starting, switching to, or combining aripiprazole with other antipsychotics or serotonergic agents (trazodone, sertraline, or venlafaxine).^27,28

Related resources

• Lieberman, J. Aripiprazole. In: Schatzberg, A, Nemeroff, C (eds.) Textbook of Psychopharmacology. Washington DC: American Psychiatric Publishing, 2004:487-494.
• FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/foi/nda/2002/21-436_Abilify.htm
• Medline Plus Drug Information. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a603012.html

Drug brand names

• Aripiprazole •Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Risperidone • Risperdal
• Trazodone • Desyrel
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

This author is supported by grant 2R25MH060490-06 from the National Institute of Mental Health.

John, age 6, presented for psychiatric evaluation with acute, incapacitating obsessive-compulsive symptoms. For 4 weeks he washed his hands compulsively and had pervasive obsessions about death by choking.

These symptoms had suddenly worsened over 2 days. At first, he washed his hands more than 35 times per day in rituals lasting several minutes each. Then, within 2 weeks, John’s handwashing spontaneously decreased, but his choking fears dramatically increased. He refused all solid foods and continuously sought reassurance from his parents that he would not choke or die.

Approximately 1 week before these symptoms began, John had a sore throat and tested positive via throat culture for group A beta-hemolytic streptococcal infection (GABHS).

Sore throat followed by sudden-onset obsessive-compulsive symptoms or tics in a child such as John suggests a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). The association between GABHS infection and these symptoms remains uncertain, as the mechanism by which GABHS infection may cause obsessive-compulsive symptoms and other childhood-onset neuropsychiatric disorders is largely unknown.

Since PANDAS was recognized (Box 1),^1-6 some data have emerged on the disorder’s symptoms, course, and prognosis. However:

• diagnostic criteria are not well-defined
  
• few controlled studies have examined treatment response
  
• using antibiotics and immunotherapies to treat or prevent PANDAS symptoms remains controversial because of unproven efficacy and potential adverse effects.
  

To help you diagnose and treat patients with suspected PANDAS, this article examines the limited evidence for the disorder, discusses diagnostic guidelines, and reviews preliminary indications for behavioral and medical treatments.

Box1

CASE REPORT CONTINUED: PANDAS CLUES

John’s sudden-onset compulsive behaviors and obsessive thoughts exemplify the rapid symptom onset often seen in children with PANDAS. His medical records showed a temporal relationship between his streptococcal infection and symptom exacerbations, which his parents confirmed. On examination, we noted choreiform movements when we asked John to extend his hands in a supinated position.

Because this was John’s first documented presentation of PANDAS-like symptoms, an additional episode would provide more convincing support for classifying his OCD as the PANDAS subtype.

DIAGNOSTIC CRITERIA

National Institute of Mental Health (NIMH) diagnostic guidelines for PANDAS,⁷ initially proposed as working guidelines by Swedo and colleagues,⁸ are listed in Table 1.

Time between GABHS infection and symptom onset varies, but post-streptococcal diseases generally emerge after a few days to several weeks.⁹ Because this latent period makes retrospective assessment difficult,¹⁰ NIMH guidelines require a prospective link between GABHS infection and at least two OCD/tic symptom episodes.^7,8,11 These additional criteria are necessary to avoid misdiagnosing PANDAS in cases when the GABHS infection/OCD connection is spurious.

Table 1

Guidelines for PANDAS diagnosis

PROSPECTIVE DIAGNOSIS

Neuropsychiatric symptoms. Early PANDAS symptoms are often similar to those of pediatric OCD and tic disorders (Table 2). Notable differences include:

• Sudden onset of obsessive-compulsive or tic behaviors shortly after GABHS infection, as opposed to OCD’s typical insidious course.
  
• Prepubertal onset (average age 7, as with Tourette’s syndrome^7,8), compared with average age 10 of childhood OCD.¹²
  

Compulsions reported in PANDAS include germ-related behaviors such as hand washing, hoarding, and excessive toilet hygiene rituals. Most studies show consistent gender differences, with more washing behaviors by girls and more checking behaviors, aggression, and tics among boys.¹³

Recurrences. PANDAS has an episodic course, and approximately 50% of patients experience recurrences.¹³ Whether PANDAS remits completely, becomes dormant when neuropsychiatric symptoms are waning, or consistently progresses to a more chronic illness is unclear.

Because young children diagnosed with PANDAS often have repeated, frequent GABHS infections,⁸ give careful attention to:

• unexplained abdominal pain accompanied by fever
  
• history of scarlet fever
  
• brief episodes of tics, OCD, or compulsive urination that remitted
  
• illness accompanied by sudden onset of OCD or tic-like behaviors
  
• history of sore throats not severe enough to seek medical attention
  
• dramatic improvement in behavior/neuropsychiatric symptoms following standard antibiotictherapy for unrelated infection.
  

Differential diagnosis of OCD, tic disorders, and PANDAS

WEIGHING TREATMENT OPTIONS

Antibiotics. Antibiotic treatment of GABHS infection has been thoroughly studied among patients with rheumatic fever. American Heart Association guidelines for preventing rheumatic fever after GABHS infection recommend oral penicillin, 250 mg bid.¹⁴ Studies also indicate that using azithromycin, 500 mg once weekly, can protect against GABHS infection but may also increase resistance to macrolide antibiotics.¹⁵

Because antibiotic prophylaxis for GABHS infection is effective for rheumatic fever, some researchers have hypothesized that similar treatment would reduce neuropsychiatric symptoms in PANDAS patients.

In a double-blind, randomized, controlled trial, Snider et al¹⁶ found significant decreases in GABHS infection and neuropsychiatric symptoms in 23 PANDAS patients who took penicillin (250 mg bid) or azithromycin (250 mg bid on one day of the week) for 12 months.

An earlier study using penicillin for PANDAS prophylaxis was inconclusive. Its design limited more-definitive conclusions by allowing a high rate of antibiotic use during the placebo phase.¹⁷

An uncontrolled prospective study by Murphy et al¹³ documented rapid resolution of primary OCD, tic, and anxiety symptoms after appropriate antibiotic treatment in 12 children with PANDAS. Obsessive-compulsive symptoms remitted 5 to 21 days after patients received penicillin, amoxicillin/clavulanate potassium, or a cephalosporin. Symptoms resolved much more quickly than nonPANDAS obsessive-compulsive and tic disorders usually remit with cognitive-behavioral, habit reversal, and/or drug treatment.¹⁸ One-half of patients had at least one OCD recurrence, all documented as GABHS-positive with throat culture or rapid antigen-detection assay.

Recommendation. Obtain a GABHS culture if a child presents with sudden-onset OCD. If positive, treat with a standard course of antibiotics.¹⁹ Caution is strongly recommended when using antibiotics in children, as antibiotic-resistant organisms may develop. Collaborate with the child’s pediatrician to ensure that strep infections are treated consistently.

CASE CONTINUED: USING CBT FOR PANDAS

Giving John antibiotics when he had the sore throat might have been a rational choice to manage acute OCD symptoms. However, the scant literature on antibiotic prophylaxis for PANDAS subtype OCD led us to also consider cognitive-behavioral therapy (CBT).

CBT alone or with a selective serotonin reuptake inhibitor (SSRI) is first-line therapy for pediatric OCD.^18,20 We hypothesized, therefore, that CBT might also be useful in PANDAS and provided John with five CBT sessions within 1 week, without giving an antibiotic or other medication. [See our study²¹ for therapy details.]

At baseline, John’s score on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) was 34, indicating severe OCD symptoms, and his score on the Anxiety/Depression subscale of the Child Behavior Checklist (CBCL) was elevated (t = 66). After five CBT sessions, John’s CY-BOCS score decreased by 75% to 8 and his CBCL Anxiety/Depression score decreased into the average range (t = 50).²¹

Given PANDAS’ fluctuating course, his symptoms could have remitted spontaneously. His symptoms remained in remission 6 months later.

We believe John’s case is the only published description of using CBT alone to treat a patient with PANDAS. Since then, our team has successfully treated several other PANDAS patients using CBT. Based on our experience with trained clinicians, CBT provided an appropriate treatment option for this handful of cases. Controlled trials are needed to establish CBT’s efficacy for treating documented PANDAS.

SSRIs. As stated, CBT alone or with an SSRI is first-line therapy for pediatric OCD, and CBT alone or with an SSRI reduces pediatric OCD symptoms more effectively than antidepressants alone.¹⁸ Because no published reports of SSRI use in PANDAS exist, we recommend treating a child with PANDAS as you would any child presenting with OCD and tics:

• For milder cases with recent onset, begin with clinical monitoring for GABHS, without using SSRIs or antibiotics. Early CBT may prevent symptom worsening.
  
• For more severecases of longer duration, continue with CBT, then consider adding an SSRI.
  

Immunomodulatory therapies? Immunomodulatory therapies such as IV immunoglobulin (IVIG) and plasma exchange are not appropriate for refractory OCD or tic cases that have no clear GABHS association and a relapsing/remitting course. No studies support using immunomodulatory agents in disorders without an immune-mediated cause.

You might consider these therapies for severe, clearly established PANDAS only when less-invasive treatments (antibiotics, standard OCD therapies) have been ineffective and then only under research protocols and by physicians experienced in giving them.

Immunomodulatory therapies interrupt autoantibodies’ actions on the CNS and have shown moderate (40% to 50%) symptom reduction in some CNS diseases. In the NIMH trial, plasma exchange was better tolerated than IVIG and provided greater symptom relief.²² However, at least one study has shown plasma exchange to be ineffective for chronic OCD.²³

USING ANTIBIOTICS FOR PANDAS

Snider and Swedo²⁴ recommend guidelines for treating PANDAS, based on risks of using antibiotics in children, research and clinical experience, and American Academy of Child and Adolescent Psychiatry practice parameters (Box 2).

Elevated streptococcal titers are common in the community population²⁵ and are not necessarily diagnostic of PANDAS. Thus, it is important to demonstrate a change in titer levels (such as a 4-fold dilution rise in antistreptococcal antibody titers 4 to 6 weeks after infection).

In patients with new-onset OCD/tics or recent symptom exacerbation, a positive throat culture provides support that symptoms were triggered by subclinical GABHS infection but does not rule out the possibility that the child is a GABHS carrier.

After streptococcal infections, titers may remain elevated for 6 months to 1 year. Murphy et al²⁵ found persistent elevations in one or more strep titers in patients with dramatically fluctuating neuropsychiatric symptoms, compared with those whose course was inconsistent with PANDAS. It is unclear if these children had undetected, frequent GABHS infections or the elevated titers reflect a chronic immune activation to GABHS.

Box 2

• National Institute of Mental Health. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).http://intramural.nimh.nih.gov/pdn/web.htm.
  
• Murphy TK, Herbstman, DM, Edge PJ. Infectious trigger in obsessive compulsive and tic disorders. In: Fatemi SH (ed). Infectious etiologies of neuropsychiatric disorders. New York: Taylor & Francis (in press).
  

• Amoxicillin/potassium clavulanate • Augmentin
  
• Azithromycin • Zithromax
  

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

Dr. Storch receives grant support from the National Institute of Health and Genentech Inc.

Dr. Murphy receives grant support from the National Institute of Mental Health, Bristol-Myers Squibb Co., and the Tourette Syndrome Association (TSA). She is a speaker for Pfizer, Inc.

John, age 6, presented for psychiatric evaluation with acute, incapacitating obsessive-compulsive symptoms. For 4 weeks he washed his hands compulsively and had pervasive obsessions about death by choking.

These symptoms had suddenly worsened over 2 days. At first, he washed his hands more than 35 times per day in rituals lasting several minutes each. Then, within 2 weeks, John’s handwashing spontaneously decreased, but his choking fears dramatically increased. He refused all solid foods and continuously sought reassurance from his parents that he would not choke or die.

Approximately 1 week before these symptoms began, John had a sore throat and tested positive via throat culture for group A beta-hemolytic streptococcal infection (GABHS).

Sore throat followed by sudden-onset obsessive-compulsive symptoms or tics in a child such as John suggests a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). The association between GABHS infection and these symptoms remains uncertain, as the mechanism by which GABHS infection may cause obsessive-compulsive symptoms and other childhood-onset neuropsychiatric disorders is largely unknown.

Since PANDAS was recognized (Box 1),^1-6 some data have emerged on the disorder’s symptoms, course, and prognosis. However:

• diagnostic criteria are not well-defined
  
• few controlled studies have examined treatment response
  
• using antibiotics and immunotherapies to treat or prevent PANDAS symptoms remains controversial because of unproven efficacy and potential adverse effects.
  

To help you diagnose and treat patients with suspected PANDAS, this article examines the limited evidence for the disorder, discusses diagnostic guidelines, and reviews preliminary indications for behavioral and medical treatments.

Box1

CASE REPORT CONTINUED: PANDAS CLUES

John’s sudden-onset compulsive behaviors and obsessive thoughts exemplify the rapid symptom onset often seen in children with PANDAS. His medical records showed a temporal relationship between his streptococcal infection and symptom exacerbations, which his parents confirmed. On examination, we noted choreiform movements when we asked John to extend his hands in a supinated position.

Because this was John’s first documented presentation of PANDAS-like symptoms, an additional episode would provide more convincing support for classifying his OCD as the PANDAS subtype.

DIAGNOSTIC CRITERIA

National Institute of Mental Health (NIMH) diagnostic guidelines for PANDAS,⁷ initially proposed as working guidelines by Swedo and colleagues,⁸ are listed in Table 1.

Time between GABHS infection and symptom onset varies, but post-streptococcal diseases generally emerge after a few days to several weeks.⁹ Because this latent period makes retrospective assessment difficult,¹⁰ NIMH guidelines require a prospective link between GABHS infection and at least two OCD/tic symptom episodes.^7,8,11 These additional criteria are necessary to avoid misdiagnosing PANDAS in cases when the GABHS infection/OCD connection is spurious.

Table 1

Guidelines for PANDAS diagnosis

PROSPECTIVE DIAGNOSIS

Neuropsychiatric symptoms. Early PANDAS symptoms are often similar to those of pediatric OCD and tic disorders (Table 2). Notable differences include:

• Sudden onset of obsessive-compulsive or tic behaviors shortly after GABHS infection, as opposed to OCD’s typical insidious course.
  
• Prepubertal onset (average age 7, as with Tourette’s syndrome^7,8), compared with average age 10 of childhood OCD.¹²
  

Compulsions reported in PANDAS include germ-related behaviors such as hand washing, hoarding, and excessive toilet hygiene rituals. Most studies show consistent gender differences, with more washing behaviors by girls and more checking behaviors, aggression, and tics among boys.¹³

Recurrences. PANDAS has an episodic course, and approximately 50% of patients experience recurrences.¹³ Whether PANDAS remits completely, becomes dormant when neuropsychiatric symptoms are waning, or consistently progresses to a more chronic illness is unclear.

Because young children diagnosed with PANDAS often have repeated, frequent GABHS infections,⁸ give careful attention to:

• unexplained abdominal pain accompanied by fever
  
• history of scarlet fever
  
• brief episodes of tics, OCD, or compulsive urination that remitted
  
• illness accompanied by sudden onset of OCD or tic-like behaviors
  
• history of sore throats not severe enough to seek medical attention
  
• dramatic improvement in behavior/neuropsychiatric symptoms following standard antibiotictherapy for unrelated infection.
  

Differential diagnosis of OCD, tic disorders, and PANDAS

WEIGHING TREATMENT OPTIONS

Antibiotics. Antibiotic treatment of GABHS infection has been thoroughly studied among patients with rheumatic fever. American Heart Association guidelines for preventing rheumatic fever after GABHS infection recommend oral penicillin, 250 mg bid.¹⁴ Studies also indicate that using azithromycin, 500 mg once weekly, can protect against GABHS infection but may also increase resistance to macrolide antibiotics.¹⁵

Because antibiotic prophylaxis for GABHS infection is effective for rheumatic fever, some researchers have hypothesized that similar treatment would reduce neuropsychiatric symptoms in PANDAS patients.

In a double-blind, randomized, controlled trial, Snider et al¹⁶ found significant decreases in GABHS infection and neuropsychiatric symptoms in 23 PANDAS patients who took penicillin (250 mg bid) or azithromycin (250 mg bid on one day of the week) for 12 months.

An earlier study using penicillin for PANDAS prophylaxis was inconclusive. Its design limited more-definitive conclusions by allowing a high rate of antibiotic use during the placebo phase.¹⁷

An uncontrolled prospective study by Murphy et al¹³ documented rapid resolution of primary OCD, tic, and anxiety symptoms after appropriate antibiotic treatment in 12 children with PANDAS. Obsessive-compulsive symptoms remitted 5 to 21 days after patients received penicillin, amoxicillin/clavulanate potassium, or a cephalosporin. Symptoms resolved much more quickly than nonPANDAS obsessive-compulsive and tic disorders usually remit with cognitive-behavioral, habit reversal, and/or drug treatment.¹⁸ One-half of patients had at least one OCD recurrence, all documented as GABHS-positive with throat culture or rapid antigen-detection assay.

Recommendation. Obtain a GABHS culture if a child presents with sudden-onset OCD. If positive, treat with a standard course of antibiotics.¹⁹ Caution is strongly recommended when using antibiotics in children, as antibiotic-resistant organisms may develop. Collaborate with the child’s pediatrician to ensure that strep infections are treated consistently.

CASE CONTINUED: USING CBT FOR PANDAS

Giving John antibiotics when he had the sore throat might have been a rational choice to manage acute OCD symptoms. However, the scant literature on antibiotic prophylaxis for PANDAS subtype OCD led us to also consider cognitive-behavioral therapy (CBT).

CBT alone or with a selective serotonin reuptake inhibitor (SSRI) is first-line therapy for pediatric OCD.^18,20 We hypothesized, therefore, that CBT might also be useful in PANDAS and provided John with five CBT sessions within 1 week, without giving an antibiotic or other medication. [See our study²¹ for therapy details.]

At baseline, John’s score on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) was 34, indicating severe OCD symptoms, and his score on the Anxiety/Depression subscale of the Child Behavior Checklist (CBCL) was elevated (t = 66). After five CBT sessions, John’s CY-BOCS score decreased by 75% to 8 and his CBCL Anxiety/Depression score decreased into the average range (t = 50).²¹

Given PANDAS’ fluctuating course, his symptoms could have remitted spontaneously. His symptoms remained in remission 6 months later.

We believe John’s case is the only published description of using CBT alone to treat a patient with PANDAS. Since then, our team has successfully treated several other PANDAS patients using CBT. Based on our experience with trained clinicians, CBT provided an appropriate treatment option for this handful of cases. Controlled trials are needed to establish CBT’s efficacy for treating documented PANDAS.

SSRIs. As stated, CBT alone or with an SSRI is first-line therapy for pediatric OCD, and CBT alone or with an SSRI reduces pediatric OCD symptoms more effectively than antidepressants alone.¹⁸ Because no published reports of SSRI use in PANDAS exist, we recommend treating a child with PANDAS as you would any child presenting with OCD and tics:

• For milder cases with recent onset, begin with clinical monitoring for GABHS, without using SSRIs or antibiotics. Early CBT may prevent symptom worsening.
  
• For more severecases of longer duration, continue with CBT, then consider adding an SSRI.
  

Immunomodulatory therapies? Immunomodulatory therapies such as IV immunoglobulin (IVIG) and plasma exchange are not appropriate for refractory OCD or tic cases that have no clear GABHS association and a relapsing/remitting course. No studies support using immunomodulatory agents in disorders without an immune-mediated cause.

You might consider these therapies for severe, clearly established PANDAS only when less-invasive treatments (antibiotics, standard OCD therapies) have been ineffective and then only under research protocols and by physicians experienced in giving them.

Immunomodulatory therapies interrupt autoantibodies’ actions on the CNS and have shown moderate (40% to 50%) symptom reduction in some CNS diseases. In the NIMH trial, plasma exchange was better tolerated than IVIG and provided greater symptom relief.²² However, at least one study has shown plasma exchange to be ineffective for chronic OCD.²³

USING ANTIBIOTICS FOR PANDAS

Snider and Swedo²⁴ recommend guidelines for treating PANDAS, based on risks of using antibiotics in children, research and clinical experience, and American Academy of Child and Adolescent Psychiatry practice parameters (Box 2).

Elevated streptococcal titers are common in the community population²⁵ and are not necessarily diagnostic of PANDAS. Thus, it is important to demonstrate a change in titer levels (such as a 4-fold dilution rise in antistreptococcal antibody titers 4 to 6 weeks after infection).

In patients with new-onset OCD/tics or recent symptom exacerbation, a positive throat culture provides support that symptoms were triggered by subclinical GABHS infection but does not rule out the possibility that the child is a GABHS carrier.

After streptococcal infections, titers may remain elevated for 6 months to 1 year. Murphy et al²⁵ found persistent elevations in one or more strep titers in patients with dramatically fluctuating neuropsychiatric symptoms, compared with those whose course was inconsistent with PANDAS. It is unclear if these children had undetected, frequent GABHS infections or the elevated titers reflect a chronic immune activation to GABHS.

Box 2

• National Institute of Mental Health. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).http://intramural.nimh.nih.gov/pdn/web.htm.
  
• Murphy TK, Herbstman, DM, Edge PJ. Infectious trigger in obsessive compulsive and tic disorders. In: Fatemi SH (ed). Infectious etiologies of neuropsychiatric disorders. New York: Taylor & Francis (in press).
  

• Amoxicillin/potassium clavulanate • Augmentin
  
• Azithromycin • Zithromax
  

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

Dr. Storch receives grant support from the National Institute of Health and Genentech Inc.

Dr. Murphy receives grant support from the National Institute of Mental Health, Bristol-Myers Squibb Co., and the Tourette Syndrome Association (TSA). She is a speaker for Pfizer, Inc.

John, age 6, presented for psychiatric evaluation with acute, incapacitating obsessive-compulsive symptoms. For 4 weeks he washed his hands compulsively and had pervasive obsessions about death by choking.

These symptoms had suddenly worsened over 2 days. At first, he washed his hands more than 35 times per day in rituals lasting several minutes each. Then, within 2 weeks, John’s handwashing spontaneously decreased, but his choking fears dramatically increased. He refused all solid foods and continuously sought reassurance from his parents that he would not choke or die.

Approximately 1 week before these symptoms began, John had a sore throat and tested positive via throat culture for group A beta-hemolytic streptococcal infection (GABHS).

Sore throat followed by sudden-onset obsessive-compulsive symptoms or tics in a child such as John suggests a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). The association between GABHS infection and these symptoms remains uncertain, as the mechanism by which GABHS infection may cause obsessive-compulsive symptoms and other childhood-onset neuropsychiatric disorders is largely unknown.

Since PANDAS was recognized (Box 1),^1-6 some data have emerged on the disorder’s symptoms, course, and prognosis. However:

• diagnostic criteria are not well-defined
  
• few controlled studies have examined treatment response
  
• using antibiotics and immunotherapies to treat or prevent PANDAS symptoms remains controversial because of unproven efficacy and potential adverse effects.
  

To help you diagnose and treat patients with suspected PANDAS, this article examines the limited evidence for the disorder, discusses diagnostic guidelines, and reviews preliminary indications for behavioral and medical treatments.

Box1

CASE REPORT CONTINUED: PANDAS CLUES

John’s sudden-onset compulsive behaviors and obsessive thoughts exemplify the rapid symptom onset often seen in children with PANDAS. His medical records showed a temporal relationship between his streptococcal infection and symptom exacerbations, which his parents confirmed. On examination, we noted choreiform movements when we asked John to extend his hands in a supinated position.

Because this was John’s first documented presentation of PANDAS-like symptoms, an additional episode would provide more convincing support for classifying his OCD as the PANDAS subtype.

DIAGNOSTIC CRITERIA

National Institute of Mental Health (NIMH) diagnostic guidelines for PANDAS,⁷ initially proposed as working guidelines by Swedo and colleagues,⁸ are listed in Table 1.

Time between GABHS infection and symptom onset varies, but post-streptococcal diseases generally emerge after a few days to several weeks.⁹ Because this latent period makes retrospective assessment difficult,¹⁰ NIMH guidelines require a prospective link between GABHS infection and at least two OCD/tic symptom episodes.^7,8,11 These additional criteria are necessary to avoid misdiagnosing PANDAS in cases when the GABHS infection/OCD connection is spurious.

Table 1

Guidelines for PANDAS diagnosis

PROSPECTIVE DIAGNOSIS

Neuropsychiatric symptoms. Early PANDAS symptoms are often similar to those of pediatric OCD and tic disorders (Table 2). Notable differences include:

• Sudden onset of obsessive-compulsive or tic behaviors shortly after GABHS infection, as opposed to OCD’s typical insidious course.
  
• Prepubertal onset (average age 7, as with Tourette’s syndrome^7,8), compared with average age 10 of childhood OCD.¹²
  

Compulsions reported in PANDAS include germ-related behaviors such as hand washing, hoarding, and excessive toilet hygiene rituals. Most studies show consistent gender differences, with more washing behaviors by girls and more checking behaviors, aggression, and tics among boys.¹³

Recurrences. PANDAS has an episodic course, and approximately 50% of patients experience recurrences.¹³ Whether PANDAS remits completely, becomes dormant when neuropsychiatric symptoms are waning, or consistently progresses to a more chronic illness is unclear.

Because young children diagnosed with PANDAS often have repeated, frequent GABHS infections,⁸ give careful attention to:

• unexplained abdominal pain accompanied by fever
  
• history of scarlet fever
  
• brief episodes of tics, OCD, or compulsive urination that remitted
  
• illness accompanied by sudden onset of OCD or tic-like behaviors
  
• history of sore throats not severe enough to seek medical attention
  
• dramatic improvement in behavior/neuropsychiatric symptoms following standard antibiotictherapy for unrelated infection.
  

Differential diagnosis of OCD, tic disorders, and PANDAS

WEIGHING TREATMENT OPTIONS

Antibiotics. Antibiotic treatment of GABHS infection has been thoroughly studied among patients with rheumatic fever. American Heart Association guidelines for preventing rheumatic fever after GABHS infection recommend oral penicillin, 250 mg bid.¹⁴ Studies also indicate that using azithromycin, 500 mg once weekly, can protect against GABHS infection but may also increase resistance to macrolide antibiotics.¹⁵

Because antibiotic prophylaxis for GABHS infection is effective for rheumatic fever, some researchers have hypothesized that similar treatment would reduce neuropsychiatric symptoms in PANDAS patients.

In a double-blind, randomized, controlled trial, Snider et al¹⁶ found significant decreases in GABHS infection and neuropsychiatric symptoms in 23 PANDAS patients who took penicillin (250 mg bid) or azithromycin (250 mg bid on one day of the week) for 12 months.

An earlier study using penicillin for PANDAS prophylaxis was inconclusive. Its design limited more-definitive conclusions by allowing a high rate of antibiotic use during the placebo phase.¹⁷

An uncontrolled prospective study by Murphy et al¹³ documented rapid resolution of primary OCD, tic, and anxiety symptoms after appropriate antibiotic treatment in 12 children with PANDAS. Obsessive-compulsive symptoms remitted 5 to 21 days after patients received penicillin, amoxicillin/clavulanate potassium, or a cephalosporin. Symptoms resolved much more quickly than nonPANDAS obsessive-compulsive and tic disorders usually remit with cognitive-behavioral, habit reversal, and/or drug treatment.¹⁸ One-half of patients had at least one OCD recurrence, all documented as GABHS-positive with throat culture or rapid antigen-detection assay.

Recommendation. Obtain a GABHS culture if a child presents with sudden-onset OCD. If positive, treat with a standard course of antibiotics.¹⁹ Caution is strongly recommended when using antibiotics in children, as antibiotic-resistant organisms may develop. Collaborate with the child’s pediatrician to ensure that strep infections are treated consistently.

CASE CONTINUED: USING CBT FOR PANDAS

Giving John antibiotics when he had the sore throat might have been a rational choice to manage acute OCD symptoms. However, the scant literature on antibiotic prophylaxis for PANDAS subtype OCD led us to also consider cognitive-behavioral therapy (CBT).

CBT alone or with a selective serotonin reuptake inhibitor (SSRI) is first-line therapy for pediatric OCD.^18,20 We hypothesized, therefore, that CBT might also be useful in PANDAS and provided John with five CBT sessions within 1 week, without giving an antibiotic or other medication. [See our study²¹ for therapy details.]

At baseline, John’s score on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) was 34, indicating severe OCD symptoms, and his score on the Anxiety/Depression subscale of the Child Behavior Checklist (CBCL) was elevated (t = 66). After five CBT sessions, John’s CY-BOCS score decreased by 75% to 8 and his CBCL Anxiety/Depression score decreased into the average range (t = 50).²¹

Given PANDAS’ fluctuating course, his symptoms could have remitted spontaneously. His symptoms remained in remission 6 months later.

We believe John’s case is the only published description of using CBT alone to treat a patient with PANDAS. Since then, our team has successfully treated several other PANDAS patients using CBT. Based on our experience with trained clinicians, CBT provided an appropriate treatment option for this handful of cases. Controlled trials are needed to establish CBT’s efficacy for treating documented PANDAS.

SSRIs. As stated, CBT alone or with an SSRI is first-line therapy for pediatric OCD, and CBT alone or with an SSRI reduces pediatric OCD symptoms more effectively than antidepressants alone.¹⁸ Because no published reports of SSRI use in PANDAS exist, we recommend treating a child with PANDAS as you would any child presenting with OCD and tics:

• For milder cases with recent onset, begin with clinical monitoring for GABHS, without using SSRIs or antibiotics. Early CBT may prevent symptom worsening.
  
• For more severecases of longer duration, continue with CBT, then consider adding an SSRI.
  

Immunomodulatory therapies? Immunomodulatory therapies such as IV immunoglobulin (IVIG) and plasma exchange are not appropriate for refractory OCD or tic cases that have no clear GABHS association and a relapsing/remitting course. No studies support using immunomodulatory agents in disorders without an immune-mediated cause.

You might consider these therapies for severe, clearly established PANDAS only when less-invasive treatments (antibiotics, standard OCD therapies) have been ineffective and then only under research protocols and by physicians experienced in giving them.

Immunomodulatory therapies interrupt autoantibodies’ actions on the CNS and have shown moderate (40% to 50%) symptom reduction in some CNS diseases. In the NIMH trial, plasma exchange was better tolerated than IVIG and provided greater symptom relief.²² However, at least one study has shown plasma exchange to be ineffective for chronic OCD.²³

USING ANTIBIOTICS FOR PANDAS

Snider and Swedo²⁴ recommend guidelines for treating PANDAS, based on risks of using antibiotics in children, research and clinical experience, and American Academy of Child and Adolescent Psychiatry practice parameters (Box 2).

Elevated streptococcal titers are common in the community population²⁵ and are not necessarily diagnostic of PANDAS. Thus, it is important to demonstrate a change in titer levels (such as a 4-fold dilution rise in antistreptococcal antibody titers 4 to 6 weeks after infection).

In patients with new-onset OCD/tics or recent symptom exacerbation, a positive throat culture provides support that symptoms were triggered by subclinical GABHS infection but does not rule out the possibility that the child is a GABHS carrier.

After streptococcal infections, titers may remain elevated for 6 months to 1 year. Murphy et al²⁵ found persistent elevations in one or more strep titers in patients with dramatically fluctuating neuropsychiatric symptoms, compared with those whose course was inconsistent with PANDAS. It is unclear if these children had undetected, frequent GABHS infections or the elevated titers reflect a chronic immune activation to GABHS.

Box 2

• National Institute of Mental Health. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).http://intramural.nimh.nih.gov/pdn/web.htm.
  
• Murphy TK, Herbstman, DM, Edge PJ. Infectious trigger in obsessive compulsive and tic disorders. In: Fatemi SH (ed). Infectious etiologies of neuropsychiatric disorders. New York: Taylor & Francis (in press).
  

• Amoxicillin/potassium clavulanate • Augmentin
  
• Azithromycin • Zithromax
  

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

Dr. Storch receives grant support from the National Institute of Health and Genentech Inc.

Dr. Murphy receives grant support from the National Institute of Mental Health, Bristol-Myers Squibb Co., and the Tourette Syndrome Association (TSA). She is a speaker for Pfizer, Inc.

Off-label prescribing of two or more antipsychotics for treatment-resistant psychosis carries inherent risks for both schizophrenia patients and their psychiatrists. You can reduce these risks by demonstrating that your patient will benefit more from combining antipsychotics than from monotherapy alternatives.

Until more empiric data become available, clinicians carry the burden of documenting individual patient response to justify combining antipsychotics. This article can help you identify and counsel possible candidates for this therapy, assess the risks and benefits, and defend your treatment choicesif necessary.

What Does ‘Combining’ Mean?

For this discussion, “combining antipsychotics” does not mean simultaneously using two or more antipsychotics to treat psychosis. Rather, it refers to using two or more antipsychotics for long-term control of psychotic symptoms. It does not apply to short-term tactics, such as overlapping antipsychotics when switching between them or combining a parenteral and an oral antipsychotic when treating an acute episode.

How long must a combination be used to qualify as long-term treatment? No standard exists, but a period >6 weeks exceeds normal short-term treatment.

How Safe Are Combinations?

Patient risk. Combination antipsychotics are used to treat 10% to 20% of schizophrenia patients in this country and >90% of those in some Asian countries, such as Japan.¹ Statistics on the prevalence of combining antipsychotics seldom:

• distinguish between short- and long-term use
  
• identify when practitioners use combinations to treat co-existing symptoms such as insomnia, rather than for psychosis.
  

Clinicians, however, must define safety in terms of risks and benefits. Given that every medication has risks—some (such as allergic reactions) unique to the individual patient—adding another drug to a treatment regimen will always add risk. When considering more than one antipsychotic, ask yourself:

• Do benefits outweigh risks?
  
• Is a combination the least risky way to achieve these benefits?
  

How much does a practitioner’s perception of medicolegal risk influence treatment selection? No doubt, comfort level varies greatly. I have frequently met prescribers who use antipsychotic combinations instead of clozapine for fear of being sued should agranulocytosis occur.

Box

A Practical View

Medical risks. Treating patients with antipsychotic combinations may be associated with medical risks (Table 1). Patients are less likely to adhere to complex medication regimens than to simple ones. Thus, adding a second antipsychotic may decrease adherence to the first antipsychotic and to other medications, such as for hypertension, diabetes, etc.

Increased side-effect risk has been reported with antipsychotic combinations.⁴ Side effects include those expected from one or both drugs in the combination, especially extrapyramidal effects when conventional antipsychotics are included.^4,5 Because the total antipsychotic dosage can be considerably higher than usual in patients receiving combinations,⁵ some of the increased side effect burden is probably related to high dosing, rather than to the combinations.

Pharmacodynamic or pharmacokinetic interactions or the loss of an agent’s advantages are infrequently reported, perhaps because prescribers are not looking for these effects or do not consider them worth reporting. Of particular concern is tardive dyskinesia (TD), which may develop when conventional antipsychotics are added to agents with very low propensity to cause TD—such as clozapine.

Table 1

Potential risks and benefits of combining antipsychotics

litigation. As noted, some clinicians prefer combining antipsychotics instead of using clozapine because they fear legal action should a patient develop agranulocytosis. In the author’s view, this fear is not well-grounded. Successful lawsuits typically find evidence that the clinician committed errors of omission or commission. In the case of blood monitoring for clozapine-induced neutropenia, the parameters are clear and enforced. You must follow community standards of practice, which provide a strong legal defense.

Administrative scrutiny. Quality assurance programs are increasingly identifying and monitoring antipsychotic combinations—an obvious target by being frequent, lacking a strong evidence base, increasing costs, and raising liability concerns. Typically, such programs discourage antipsychotic combinations and impose administrative hurdles to starting or continuing them.

Gathering data and documenting it in the patient’s medical record—to be discussed later—is key to demonstrating that a combination’s superior efficacy for the individual patient justifies its use.

Medical benefits. Guidelines and algorithms for drug treatment of schizophrenia either omit combination antipsychotics or suggest this strategy when all else has failed.^6,7 Lack of evidence for a practice is not the same as evidence against it, however. A combination may be better for some patients than any available antipsychotic monotherapy.

Antipsychotic combinations have been examined in more literature reviews than randomized controlled trials—all of which have addressed augmenting clozapine with another antipsychotic (Table 2).^8-12 Augmentation with psychotropics other than a second antipsychotic has most often been tested for negative and cognitive symptoms,⁴ but some evidence has shown adjunctive anticonvulsants and cognition-enhancing agents to improve positive symptoms.⁶

Reducing side effects is not directly related to treatment-resistant psychosis, but some articles describe managing clozapine’s metabolic side effects by partially substituting another atypical antipsychotic.^11,13

Because clozapine is the treatment of choice for treatment-resistant psychosis, consider tactics that maintain its benefits while reducing its metabolic liabilities. Reducing the clozapine dosage (if feasible) is the first-line approach, but partially substituting another antipsychotic might help if psychotic symptoms return.

Table 2

Results of studies using combination antipsychotic therapy

Clinical Management Hints

Document, document, document. Crucial to “non-standard” treatments such as combining antipsychotics is using and documenting good medical practices. These include:

• accurately assessing patients
  
• carefully weighing illness risks vs treatment risks
  
• talking regularly to patients about their treatment and therapeutic options (Table 3).
  

Use objective measures. Brief scales to measure psychotic symptoms are being increasingly used in public mental health settings.⁶ For example, four psychosis items from the Brief Psychiatric Rating Scale (hallucinations, unusual thought content, paranoia, and disorganized thought) can quickly assess and capture much of the variance of the full scale in patients with schizophrenia.¹⁴

When properly used, these objective and reliable scales can document clinical change and track illness course across time and providers. Other objective outcome measures can contribute to quality of care and its documentation. For more information, visit the Substance Abuse and Mental Health Services Administration Web site (see Related Resources).

Although it seems obvious that persistent illness is not a good thing, the risks of persistent psychosis vary from patient to patient. Some function relatively well despite ongoing psychotic thoughts, whereas others are terribly impaired, demoralized, and/or suicidal. The rationale for nonstandard treatment such as an antipsychotic combination is to reduce patient suffering and risk and/or to increase function.

Discuss options with patients. Finally, schizophrenia patients (and involved significant others) need to understand and participate in treatment. Ongoing discussion of treatment options is an important part of this process. For example, initially reluctant patients often come to accept clozapine treatment after discussing its risks and benefits with clinicians and other patients who are taking clozapine. Documenting these discussions is as beneficial to the patient and clinician as is documenting symptoms and treatment effects.

Table 3

3 tips for managing risk and medications

• How to use medication in a systematic and effective way, as part of the overall treatment for severe mental illness. In: Evidence-based practices: Shaping mental health services toward recovery. Medication management approaches in psychiatry. Substance Abuse and Mental Health Services Administration. U.S. Department of Health and Human Services. http://mentalhealth.samhsa.gov/cmhs/communitysupport/toolkits/medication/.
  
• Texas Medication Algorithm Project (TMAP). http://www.dshs.state.tx.us/mhprograms/TIMA.shtm.
  
• Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Am J Psychiatry 2004;161(suppl):1–56.
  

• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Dr. Miller receives research support from or is a consultant or speaker for Abbott Laboratories, Almirall, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Pfizer Inc., and InforMedix.

Off-label prescribing of two or more antipsychotics for treatment-resistant psychosis carries inherent risks for both schizophrenia patients and their psychiatrists. You can reduce these risks by demonstrating that your patient will benefit more from combining antipsychotics than from monotherapy alternatives.

Until more empiric data become available, clinicians carry the burden of documenting individual patient response to justify combining antipsychotics. This article can help you identify and counsel possible candidates for this therapy, assess the risks and benefits, and defend your treatment choicesif necessary.

What Does ‘Combining’ Mean?

For this discussion, “combining antipsychotics” does not mean simultaneously using two or more antipsychotics to treat psychosis. Rather, it refers to using two or more antipsychotics for long-term control of psychotic symptoms. It does not apply to short-term tactics, such as overlapping antipsychotics when switching between them or combining a parenteral and an oral antipsychotic when treating an acute episode.

How long must a combination be used to qualify as long-term treatment? No standard exists, but a period >6 weeks exceeds normal short-term treatment.

How Safe Are Combinations?

Patient risk. Combination antipsychotics are used to treat 10% to 20% of schizophrenia patients in this country and >90% of those in some Asian countries, such as Japan.¹ Statistics on the prevalence of combining antipsychotics seldom:

• distinguish between short- and long-term use
  
• identify when practitioners use combinations to treat co-existing symptoms such as insomnia, rather than for psychosis.
  

Clinicians, however, must define safety in terms of risks and benefits. Given that every medication has risks—some (such as allergic reactions) unique to the individual patient—adding another drug to a treatment regimen will always add risk. When considering more than one antipsychotic, ask yourself:

• Do benefits outweigh risks?
  
• Is a combination the least risky way to achieve these benefits?
  

How much does a practitioner’s perception of medicolegal risk influence treatment selection? No doubt, comfort level varies greatly. I have frequently met prescribers who use antipsychotic combinations instead of clozapine for fear of being sued should agranulocytosis occur.

Box

A Practical View

Medical risks. Treating patients with antipsychotic combinations may be associated with medical risks (Table 1). Patients are less likely to adhere to complex medication regimens than to simple ones. Thus, adding a second antipsychotic may decrease adherence to the first antipsychotic and to other medications, such as for hypertension, diabetes, etc.

Increased side-effect risk has been reported with antipsychotic combinations.⁴ Side effects include those expected from one or both drugs in the combination, especially extrapyramidal effects when conventional antipsychotics are included.^4,5 Because the total antipsychotic dosage can be considerably higher than usual in patients receiving combinations,⁵ some of the increased side effect burden is probably related to high dosing, rather than to the combinations.

Pharmacodynamic or pharmacokinetic interactions or the loss of an agent’s advantages are infrequently reported, perhaps because prescribers are not looking for these effects or do not consider them worth reporting. Of particular concern is tardive dyskinesia (TD), which may develop when conventional antipsychotics are added to agents with very low propensity to cause TD—such as clozapine.

Table 1

Potential risks and benefits of combining antipsychotics

litigation. As noted, some clinicians prefer combining antipsychotics instead of using clozapine because they fear legal action should a patient develop agranulocytosis. In the author’s view, this fear is not well-grounded. Successful lawsuits typically find evidence that the clinician committed errors of omission or commission. In the case of blood monitoring for clozapine-induced neutropenia, the parameters are clear and enforced. You must follow community standards of practice, which provide a strong legal defense.

Administrative scrutiny. Quality assurance programs are increasingly identifying and monitoring antipsychotic combinations—an obvious target by being frequent, lacking a strong evidence base, increasing costs, and raising liability concerns. Typically, such programs discourage antipsychotic combinations and impose administrative hurdles to starting or continuing them.

Gathering data and documenting it in the patient’s medical record—to be discussed later—is key to demonstrating that a combination’s superior efficacy for the individual patient justifies its use.

Medical benefits. Guidelines and algorithms for drug treatment of schizophrenia either omit combination antipsychotics or suggest this strategy when all else has failed.^6,7 Lack of evidence for a practice is not the same as evidence against it, however. A combination may be better for some patients than any available antipsychotic monotherapy.

Antipsychotic combinations have been examined in more literature reviews than randomized controlled trials—all of which have addressed augmenting clozapine with another antipsychotic (Table 2).^8-12 Augmentation with psychotropics other than a second antipsychotic has most often been tested for negative and cognitive symptoms,⁴ but some evidence has shown adjunctive anticonvulsants and cognition-enhancing agents to improve positive symptoms.⁶

Reducing side effects is not directly related to treatment-resistant psychosis, but some articles describe managing clozapine’s metabolic side effects by partially substituting another atypical antipsychotic.^11,13

Because clozapine is the treatment of choice for treatment-resistant psychosis, consider tactics that maintain its benefits while reducing its metabolic liabilities. Reducing the clozapine dosage (if feasible) is the first-line approach, but partially substituting another antipsychotic might help if psychotic symptoms return.

Table 2

Results of studies using combination antipsychotic therapy

Clinical Management Hints

Document, document, document. Crucial to “non-standard” treatments such as combining antipsychotics is using and documenting good medical practices. These include:

• accurately assessing patients
  
• carefully weighing illness risks vs treatment risks
  
• talking regularly to patients about their treatment and therapeutic options (Table 3).
  

Use objective measures. Brief scales to measure psychotic symptoms are being increasingly used in public mental health settings.⁶ For example, four psychosis items from the Brief Psychiatric Rating Scale (hallucinations, unusual thought content, paranoia, and disorganized thought) can quickly assess and capture much of the variance of the full scale in patients with schizophrenia.¹⁴

When properly used, these objective and reliable scales can document clinical change and track illness course across time and providers. Other objective outcome measures can contribute to quality of care and its documentation. For more information, visit the Substance Abuse and Mental Health Services Administration Web site (see Related Resources).

Although it seems obvious that persistent illness is not a good thing, the risks of persistent psychosis vary from patient to patient. Some function relatively well despite ongoing psychotic thoughts, whereas others are terribly impaired, demoralized, and/or suicidal. The rationale for nonstandard treatment such as an antipsychotic combination is to reduce patient suffering and risk and/or to increase function.

Discuss options with patients. Finally, schizophrenia patients (and involved significant others) need to understand and participate in treatment. Ongoing discussion of treatment options is an important part of this process. For example, initially reluctant patients often come to accept clozapine treatment after discussing its risks and benefits with clinicians and other patients who are taking clozapine. Documenting these discussions is as beneficial to the patient and clinician as is documenting symptoms and treatment effects.

Table 3

3 tips for managing risk and medications

• How to use medication in a systematic and effective way, as part of the overall treatment for severe mental illness. In: Evidence-based practices: Shaping mental health services toward recovery. Medication management approaches in psychiatry. Substance Abuse and Mental Health Services Administration. U.S. Department of Health and Human Services. http://mentalhealth.samhsa.gov/cmhs/communitysupport/toolkits/medication/.
  
• Texas Medication Algorithm Project (TMAP). http://www.dshs.state.tx.us/mhprograms/TIMA.shtm.
  
• Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Am J Psychiatry 2004;161(suppl):1–56.
  

• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Dr. Miller receives research support from or is a consultant or speaker for Abbott Laboratories, Almirall, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Pfizer Inc., and InforMedix.

Off-label prescribing of two or more antipsychotics for treatment-resistant psychosis carries inherent risks for both schizophrenia patients and their psychiatrists. You can reduce these risks by demonstrating that your patient will benefit more from combining antipsychotics than from monotherapy alternatives.

Until more empiric data become available, clinicians carry the burden of documenting individual patient response to justify combining antipsychotics. This article can help you identify and counsel possible candidates for this therapy, assess the risks and benefits, and defend your treatment choicesif necessary.

What Does ‘Combining’ Mean?

For this discussion, “combining antipsychotics” does not mean simultaneously using two or more antipsychotics to treat psychosis. Rather, it refers to using two or more antipsychotics for long-term control of psychotic symptoms. It does not apply to short-term tactics, such as overlapping antipsychotics when switching between them or combining a parenteral and an oral antipsychotic when treating an acute episode.

How long must a combination be used to qualify as long-term treatment? No standard exists, but a period >6 weeks exceeds normal short-term treatment.

How Safe Are Combinations?

Patient risk. Combination antipsychotics are used to treat 10% to 20% of schizophrenia patients in this country and >90% of those in some Asian countries, such as Japan.¹ Statistics on the prevalence of combining antipsychotics seldom:

• distinguish between short- and long-term use
  
• identify when practitioners use combinations to treat co-existing symptoms such as insomnia, rather than for psychosis.
  

Clinicians, however, must define safety in terms of risks and benefits. Given that every medication has risks—some (such as allergic reactions) unique to the individual patient—adding another drug to a treatment regimen will always add risk. When considering more than one antipsychotic, ask yourself:

• Do benefits outweigh risks?
  
• Is a combination the least risky way to achieve these benefits?
  

How much does a practitioner’s perception of medicolegal risk influence treatment selection? No doubt, comfort level varies greatly. I have frequently met prescribers who use antipsychotic combinations instead of clozapine for fear of being sued should agranulocytosis occur.

Box

A Practical View

Medical risks. Treating patients with antipsychotic combinations may be associated with medical risks (Table 1). Patients are less likely to adhere to complex medication regimens than to simple ones. Thus, adding a second antipsychotic may decrease adherence to the first antipsychotic and to other medications, such as for hypertension, diabetes, etc.

Increased side-effect risk has been reported with antipsychotic combinations.⁴ Side effects include those expected from one or both drugs in the combination, especially extrapyramidal effects when conventional antipsychotics are included.^4,5 Because the total antipsychotic dosage can be considerably higher than usual in patients receiving combinations,⁵ some of the increased side effect burden is probably related to high dosing, rather than to the combinations.

Pharmacodynamic or pharmacokinetic interactions or the loss of an agent’s advantages are infrequently reported, perhaps because prescribers are not looking for these effects or do not consider them worth reporting. Of particular concern is tardive dyskinesia (TD), which may develop when conventional antipsychotics are added to agents with very low propensity to cause TD—such as clozapine.

Table 1

Potential risks and benefits of combining antipsychotics

litigation. As noted, some clinicians prefer combining antipsychotics instead of using clozapine because they fear legal action should a patient develop agranulocytosis. In the author’s view, this fear is not well-grounded. Successful lawsuits typically find evidence that the clinician committed errors of omission or commission. In the case of blood monitoring for clozapine-induced neutropenia, the parameters are clear and enforced. You must follow community standards of practice, which provide a strong legal defense.

Administrative scrutiny. Quality assurance programs are increasingly identifying and monitoring antipsychotic combinations—an obvious target by being frequent, lacking a strong evidence base, increasing costs, and raising liability concerns. Typically, such programs discourage antipsychotic combinations and impose administrative hurdles to starting or continuing them.

Gathering data and documenting it in the patient’s medical record—to be discussed later—is key to demonstrating that a combination’s superior efficacy for the individual patient justifies its use.

Medical benefits. Guidelines and algorithms for drug treatment of schizophrenia either omit combination antipsychotics or suggest this strategy when all else has failed.^6,7 Lack of evidence for a practice is not the same as evidence against it, however. A combination may be better for some patients than any available antipsychotic monotherapy.

Antipsychotic combinations have been examined in more literature reviews than randomized controlled trials—all of which have addressed augmenting clozapine with another antipsychotic (Table 2).^8-12 Augmentation with psychotropics other than a second antipsychotic has most often been tested for negative and cognitive symptoms,⁴ but some evidence has shown adjunctive anticonvulsants and cognition-enhancing agents to improve positive symptoms.⁶

Reducing side effects is not directly related to treatment-resistant psychosis, but some articles describe managing clozapine’s metabolic side effects by partially substituting another atypical antipsychotic.^11,13

Because clozapine is the treatment of choice for treatment-resistant psychosis, consider tactics that maintain its benefits while reducing its metabolic liabilities. Reducing the clozapine dosage (if feasible) is the first-line approach, but partially substituting another antipsychotic might help if psychotic symptoms return.

Table 2

Results of studies using combination antipsychotic therapy

Clinical Management Hints

Document, document, document. Crucial to “non-standard” treatments such as combining antipsychotics is using and documenting good medical practices. These include:

• accurately assessing patients
  
• carefully weighing illness risks vs treatment risks
  
• talking regularly to patients about their treatment and therapeutic options (Table 3).
  

Use objective measures. Brief scales to measure psychotic symptoms are being increasingly used in public mental health settings.⁶ For example, four psychosis items from the Brief Psychiatric Rating Scale (hallucinations, unusual thought content, paranoia, and disorganized thought) can quickly assess and capture much of the variance of the full scale in patients with schizophrenia.¹⁴

When properly used, these objective and reliable scales can document clinical change and track illness course across time and providers. Other objective outcome measures can contribute to quality of care and its documentation. For more information, visit the Substance Abuse and Mental Health Services Administration Web site (see Related Resources).

Although it seems obvious that persistent illness is not a good thing, the risks of persistent psychosis vary from patient to patient. Some function relatively well despite ongoing psychotic thoughts, whereas others are terribly impaired, demoralized, and/or suicidal. The rationale for nonstandard treatment such as an antipsychotic combination is to reduce patient suffering and risk and/or to increase function.

Discuss options with patients. Finally, schizophrenia patients (and involved significant others) need to understand and participate in treatment. Ongoing discussion of treatment options is an important part of this process. For example, initially reluctant patients often come to accept clozapine treatment after discussing its risks and benefits with clinicians and other patients who are taking clozapine. Documenting these discussions is as beneficial to the patient and clinician as is documenting symptoms and treatment effects.

Table 3

3 tips for managing risk and medications

• How to use medication in a systematic and effective way, as part of the overall treatment for severe mental illness. In: Evidence-based practices: Shaping mental health services toward recovery. Medication management approaches in psychiatry. Substance Abuse and Mental Health Services Administration. U.S. Department of Health and Human Services. http://mentalhealth.samhsa.gov/cmhs/communitysupport/toolkits/medication/.
  
• Texas Medication Algorithm Project (TMAP). http://www.dshs.state.tx.us/mhprograms/TIMA.shtm.
  
• Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Am J Psychiatry 2004;161(suppl):1–56.
  

• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Ziprasidone • Geodon
  

Dr. Miller receives research support from or is a consultant or speaker for Abbott Laboratories, Almirall, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Pfizer Inc., and InforMedix.

Biomarkers can help psychiatrists monitor abstinence and detect relapse in patients with alcohol use disorders. A blood test that measures carbohydrate-deficient transferrin percentage (%CDT) is FDA-approved for detecting heavy drinking (Table 1)¹ and has shown effectiveness in several medical and surgical uses.

Table 1

%CDT test: Fast facts

HOW %CDT SIGNALS ALCOHOL ABUSE

In 1976, Swedish researchers detected transferrin fractions in the CSF of alcoholic patients but not in nonalcoholics.² One of these fractions was also present in alcoholics’ serum. This discovery led to the CDT biomarker.

%CDT testing is based on the finding that consuming an average >60 grams of alcohol (about 5 standard drinks) daily for ≥ 2 weeks causes a higher percentage of transferrin—a glycoprotein that transports iron in the blood—to lack its usual carbohydrate content. Transferrin appears in 6 isoforms, and studies have shown that heavy drinking increases three of these—asialo, mono sialo, and disialo transferrin—a state collectively called “carbohydrate-deficient.”

A %CDT reading ≥ 2.6 indicates that a patient may have had on average at least 5 alcoholic drinks daily for ≥ 2 weeks. Because CDT has a short mean half-life (7 to 14 days), readings >2.6 may suggest much heavier drinking at some time before the blood sample was taken.

Microcolumn chromatography separation assays that measure CDT as a percentage of total circulating transferrin have replaced initial CDT assays that used isoelectric focusing separation and immunoassay systems. This advance corrected for individual transferrin level variations.

CLINICAL USE

The %CDT test has shown effectiveness in several medical and surgical uses, including

• screening patients with diseases possibly triggered by alcohol use, such as treatment-resistant hypertension, gastroesophageal reflux disease, or depression
• detecting alcohol-use disorders in hospitalized patients
• screening presurgical and trauma patients to predict alcohol withdrawal syndrome and/or postsurgical complications.^3,4

Although no alcohol biomarker alone reliably confirms alcohol abuse/dependence, %CDT can corroborate initial clinical impressions, especially when the patient’s self-report is suspect or information from significant others is not available.

Among biomarkers, %CDT most accurately predicts alcohol withdrawal syndrome in men (mean corpuscular volume [MCV] measurements are more accurate in women).⁴ During psychiatric consults, the test may help confirm suspected alcohol use in patients admitted to inpatient medical, surgical, or trauma units.

%CDT may also help monitor abstinence when treating an alcohol use disorder. In a major prospective treatment outcome study, %CDT was more sensitive than gamma-glutamyltransferase (GGT) in detecting relapse in male but not female alcoholics.⁵ Patients who abstained from drinking for 12 weeks showed a 30% decrease in %CDT. Subjects who relapsed during treatment later showed a 60% increase in %CDT, indicating sustained heavy drinking.

%CDT decreased over the first 4 weeks of treatment and continued to decline over time for abstinent patients (Figure). After week 4, %CDT increased again for those who consumed ≥ 5 drinks per day or had a full-blown relapse.⁵

Together, routine %CDT and GGT testing during treatment and follow-up can help clinicians monitor a patient’s progress and provide accurate reports to courts, child welfare agencies, and programs for impaired professionals. A 30% reduction from baseline in either biomarker indicates abstinence or significantly reduced alcohol consumption, whereas a 30% increase suggests relapse.⁶ Consider all clinical information in the final analysis, however.

%CDT results also provide an objective basis for discussing relapses with patients. Those who are responding to treatment often welcome %CDT testing as proof they are abstaining from alcohol.

Figure %CDT changes with alcohol use or abstinence

CLINICAL PRACTICALITY

The %CDT test is an immunoassay with ion-exchange column separation followed by turbidimetric measurement. Because the procedure is complex, laboratories generally require 24 to 72 hours to test the sample.

Because the %CDT test is relatively new, pricing, reimbursement rates, and availability are not well established. Pricing will likely vary widely from state to state and among laboratories and insurers. Medicare reimburses approximately $25 for %CDT testing, compared with $10 for GGT testing.

Only select reference laboratories offer %CDT testing, but the test should become more widely available over time (Table 1).

SENSITIVITY AND SPECIFICITY

%CDT test sensitivity is 70% to 90% in male inpatient alcoholics (usually drinking within 4 to 7 days of blood draw), with specificities >90%. Sensitivity is 12% to 40% in general populations—among whom underreporting of drinking may lead to more false positives—and 40% to 60% in outpatient alcoholics.^7,8 Specificity, however, remains high—80% to 90%—when sensitivity is reduced.

Overall, %CDT is as sensitive as GGT and more sensitive than other biomarkers, including MCV, aspartate transaminase, and alanine transaminase.⁹ %CDT is more specific than GGT (92% vs. 75%) and other biomarkers. %CDT appears to be more sensitive in men, whereas GGT is more sensitive in women (Table 2).¹⁰

Ample evidence, however, suggests that %CDT and GGT readings together may provide a comprehensive picture of recent alcohol abuse.¹⁰ Whereas frequent drinking alters %CDT, GGT signals drinking intensity and is more effective at detecting episodic binge drinking (Table 2). This probably explains why problem drinkers age <20—who typically binge-drink—show little or no change in %CDT.

Table 2

%CDT vs GGT testing for recent alcohol abuse

FACTORS THAT ALTER RESULTS

Unlike GGT and MCV, few medical conditions distort %CDT,¹¹ meaning the test is accurate in patients with most medical conditions. Only end-stage liver disease, biliary cirrhosis, and rare genetic transferrin variants alter %CDT.

Women tend to have higher and more-variable CDT values than do men, possibly because of variability in normal transferrin levels, anemia secondary to iron deficiency, pregnancy, use of oral contraceptives, or menopause. %CDT cutoff scores are not gender-specific, however, because percentage rather than absolute CDT is typically measured.

%CDT seems to decrease slightly as body mass index increases, suggesting a small but significant inverse relationship between weight and %CDT. Smoking seems to raise %CDT values slightly. The specifics of and reasons for these relationships are unclear.

Related resources

• Axis-Shield. www.axis-shield.com. Click on “Lab diagnostics,” then “Alcohol-related.”

Disclosure

Dr. Anton is a consultant to Axis-Shield.

Dr. Miller and Ms. Dominick report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Biomarkers can help psychiatrists monitor abstinence and detect relapse in patients with alcohol use disorders. A blood test that measures carbohydrate-deficient transferrin percentage (%CDT) is FDA-approved for detecting heavy drinking (Table 1)¹ and has shown effectiveness in several medical and surgical uses.

Table 1

%CDT test: Fast facts

HOW %CDT SIGNALS ALCOHOL ABUSE

In 1976, Swedish researchers detected transferrin fractions in the CSF of alcoholic patients but not in nonalcoholics.² One of these fractions was also present in alcoholics’ serum. This discovery led to the CDT biomarker.

%CDT testing is based on the finding that consuming an average >60 grams of alcohol (about 5 standard drinks) daily for ≥ 2 weeks causes a higher percentage of transferrin—a glycoprotein that transports iron in the blood—to lack its usual carbohydrate content. Transferrin appears in 6 isoforms, and studies have shown that heavy drinking increases three of these—asialo, mono sialo, and disialo transferrin—a state collectively called “carbohydrate-deficient.”

A %CDT reading ≥ 2.6 indicates that a patient may have had on average at least 5 alcoholic drinks daily for ≥ 2 weeks. Because CDT has a short mean half-life (7 to 14 days), readings >2.6 may suggest much heavier drinking at some time before the blood sample was taken.

Microcolumn chromatography separation assays that measure CDT as a percentage of total circulating transferrin have replaced initial CDT assays that used isoelectric focusing separation and immunoassay systems. This advance corrected for individual transferrin level variations.

CLINICAL USE

The %CDT test has shown effectiveness in several medical and surgical uses, including

• screening patients with diseases possibly triggered by alcohol use, such as treatment-resistant hypertension, gastroesophageal reflux disease, or depression
• detecting alcohol-use disorders in hospitalized patients
• screening presurgical and trauma patients to predict alcohol withdrawal syndrome and/or postsurgical complications.^3,4

Although no alcohol biomarker alone reliably confirms alcohol abuse/dependence, %CDT can corroborate initial clinical impressions, especially when the patient’s self-report is suspect or information from significant others is not available.

Among biomarkers, %CDT most accurately predicts alcohol withdrawal syndrome in men (mean corpuscular volume [MCV] measurements are more accurate in women).⁴ During psychiatric consults, the test may help confirm suspected alcohol use in patients admitted to inpatient medical, surgical, or trauma units.

%CDT may also help monitor abstinence when treating an alcohol use disorder. In a major prospective treatment outcome study, %CDT was more sensitive than gamma-glutamyltransferase (GGT) in detecting relapse in male but not female alcoholics.⁵ Patients who abstained from drinking for 12 weeks showed a 30% decrease in %CDT. Subjects who relapsed during treatment later showed a 60% increase in %CDT, indicating sustained heavy drinking.

%CDT decreased over the first 4 weeks of treatment and continued to decline over time for abstinent patients (Figure). After week 4, %CDT increased again for those who consumed ≥ 5 drinks per day or had a full-blown relapse.⁵

Together, routine %CDT and GGT testing during treatment and follow-up can help clinicians monitor a patient’s progress and provide accurate reports to courts, child welfare agencies, and programs for impaired professionals. A 30% reduction from baseline in either biomarker indicates abstinence or significantly reduced alcohol consumption, whereas a 30% increase suggests relapse.⁶ Consider all clinical information in the final analysis, however.

%CDT results also provide an objective basis for discussing relapses with patients. Those who are responding to treatment often welcome %CDT testing as proof they are abstaining from alcohol.

Figure %CDT changes with alcohol use or abstinence

CLINICAL PRACTICALITY

The %CDT test is an immunoassay with ion-exchange column separation followed by turbidimetric measurement. Because the procedure is complex, laboratories generally require 24 to 72 hours to test the sample.

Because the %CDT test is relatively new, pricing, reimbursement rates, and availability are not well established. Pricing will likely vary widely from state to state and among laboratories and insurers. Medicare reimburses approximately $25 for %CDT testing, compared with $10 for GGT testing.

Only select reference laboratories offer %CDT testing, but the test should become more widely available over time (Table 1).

SENSITIVITY AND SPECIFICITY

%CDT test sensitivity is 70% to 90% in male inpatient alcoholics (usually drinking within 4 to 7 days of blood draw), with specificities >90%. Sensitivity is 12% to 40% in general populations—among whom underreporting of drinking may lead to more false positives—and 40% to 60% in outpatient alcoholics.^7,8 Specificity, however, remains high—80% to 90%—when sensitivity is reduced.

Overall, %CDT is as sensitive as GGT and more sensitive than other biomarkers, including MCV, aspartate transaminase, and alanine transaminase.⁹ %CDT is more specific than GGT (92% vs. 75%) and other biomarkers. %CDT appears to be more sensitive in men, whereas GGT is more sensitive in women (Table 2).¹⁰

Ample evidence, however, suggests that %CDT and GGT readings together may provide a comprehensive picture of recent alcohol abuse.¹⁰ Whereas frequent drinking alters %CDT, GGT signals drinking intensity and is more effective at detecting episodic binge drinking (Table 2). This probably explains why problem drinkers age <20—who typically binge-drink—show little or no change in %CDT.

Table 2

%CDT vs GGT testing for recent alcohol abuse

FACTORS THAT ALTER RESULTS

Unlike GGT and MCV, few medical conditions distort %CDT,¹¹ meaning the test is accurate in patients with most medical conditions. Only end-stage liver disease, biliary cirrhosis, and rare genetic transferrin variants alter %CDT.

Women tend to have higher and more-variable CDT values than do men, possibly because of variability in normal transferrin levels, anemia secondary to iron deficiency, pregnancy, use of oral contraceptives, or menopause. %CDT cutoff scores are not gender-specific, however, because percentage rather than absolute CDT is typically measured.

%CDT seems to decrease slightly as body mass index increases, suggesting a small but significant inverse relationship between weight and %CDT. Smoking seems to raise %CDT values slightly. The specifics of and reasons for these relationships are unclear.

Related resources

• Axis-Shield. www.axis-shield.com. Click on “Lab diagnostics,” then “Alcohol-related.”

Disclosure

Dr. Anton is a consultant to Axis-Shield.

Dr. Miller and Ms. Dominick report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Biomarkers can help psychiatrists monitor abstinence and detect relapse in patients with alcohol use disorders. A blood test that measures carbohydrate-deficient transferrin percentage (%CDT) is FDA-approved for detecting heavy drinking (Table 1)¹ and has shown effectiveness in several medical and surgical uses.

Table 1

%CDT test: Fast facts

HOW %CDT SIGNALS ALCOHOL ABUSE

In 1976, Swedish researchers detected transferrin fractions in the CSF of alcoholic patients but not in nonalcoholics.² One of these fractions was also present in alcoholics’ serum. This discovery led to the CDT biomarker.

%CDT testing is based on the finding that consuming an average >60 grams of alcohol (about 5 standard drinks) daily for ≥ 2 weeks causes a higher percentage of transferrin—a glycoprotein that transports iron in the blood—to lack its usual carbohydrate content. Transferrin appears in 6 isoforms, and studies have shown that heavy drinking increases three of these—asialo, mono sialo, and disialo transferrin—a state collectively called “carbohydrate-deficient.”

A %CDT reading ≥ 2.6 indicates that a patient may have had on average at least 5 alcoholic drinks daily for ≥ 2 weeks. Because CDT has a short mean half-life (7 to 14 days), readings >2.6 may suggest much heavier drinking at some time before the blood sample was taken.

Microcolumn chromatography separation assays that measure CDT as a percentage of total circulating transferrin have replaced initial CDT assays that used isoelectric focusing separation and immunoassay systems. This advance corrected for individual transferrin level variations.

CLINICAL USE

The %CDT test has shown effectiveness in several medical and surgical uses, including

• screening patients with diseases possibly triggered by alcohol use, such as treatment-resistant hypertension, gastroesophageal reflux disease, or depression
• detecting alcohol-use disorders in hospitalized patients
• screening presurgical and trauma patients to predict alcohol withdrawal syndrome and/or postsurgical complications.^3,4

Although no alcohol biomarker alone reliably confirms alcohol abuse/dependence, %CDT can corroborate initial clinical impressions, especially when the patient’s self-report is suspect or information from significant others is not available.

Among biomarkers, %CDT most accurately predicts alcohol withdrawal syndrome in men (mean corpuscular volume [MCV] measurements are more accurate in women).⁴ During psychiatric consults, the test may help confirm suspected alcohol use in patients admitted to inpatient medical, surgical, or trauma units.

%CDT may also help monitor abstinence when treating an alcohol use disorder. In a major prospective treatment outcome study, %CDT was more sensitive than gamma-glutamyltransferase (GGT) in detecting relapse in male but not female alcoholics.⁵ Patients who abstained from drinking for 12 weeks showed a 30% decrease in %CDT. Subjects who relapsed during treatment later showed a 60% increase in %CDT, indicating sustained heavy drinking.

%CDT decreased over the first 4 weeks of treatment and continued to decline over time for abstinent patients (Figure). After week 4, %CDT increased again for those who consumed ≥ 5 drinks per day or had a full-blown relapse.⁵

Together, routine %CDT and GGT testing during treatment and follow-up can help clinicians monitor a patient’s progress and provide accurate reports to courts, child welfare agencies, and programs for impaired professionals. A 30% reduction from baseline in either biomarker indicates abstinence or significantly reduced alcohol consumption, whereas a 30% increase suggests relapse.⁶ Consider all clinical information in the final analysis, however.

%CDT results also provide an objective basis for discussing relapses with patients. Those who are responding to treatment often welcome %CDT testing as proof they are abstaining from alcohol.

Figure %CDT changes with alcohol use or abstinence

CLINICAL PRACTICALITY

The %CDT test is an immunoassay with ion-exchange column separation followed by turbidimetric measurement. Because the procedure is complex, laboratories generally require 24 to 72 hours to test the sample.

Because the %CDT test is relatively new, pricing, reimbursement rates, and availability are not well established. Pricing will likely vary widely from state to state and among laboratories and insurers. Medicare reimburses approximately $25 for %CDT testing, compared with $10 for GGT testing.

Only select reference laboratories offer %CDT testing, but the test should become more widely available over time (Table 1).

SENSITIVITY AND SPECIFICITY

%CDT test sensitivity is 70% to 90% in male inpatient alcoholics (usually drinking within 4 to 7 days of blood draw), with specificities >90%. Sensitivity is 12% to 40% in general populations—among whom underreporting of drinking may lead to more false positives—and 40% to 60% in outpatient alcoholics.^7,8 Specificity, however, remains high—80% to 90%—when sensitivity is reduced.

Overall, %CDT is as sensitive as GGT and more sensitive than other biomarkers, including MCV, aspartate transaminase, and alanine transaminase.⁹ %CDT is more specific than GGT (92% vs. 75%) and other biomarkers. %CDT appears to be more sensitive in men, whereas GGT is more sensitive in women (Table 2).¹⁰

Ample evidence, however, suggests that %CDT and GGT readings together may provide a comprehensive picture of recent alcohol abuse.¹⁰ Whereas frequent drinking alters %CDT, GGT signals drinking intensity and is more effective at detecting episodic binge drinking (Table 2). This probably explains why problem drinkers age <20—who typically binge-drink—show little or no change in %CDT.

Table 2

%CDT vs GGT testing for recent alcohol abuse

FACTORS THAT ALTER RESULTS

Unlike GGT and MCV, few medical conditions distort %CDT,¹¹ meaning the test is accurate in patients with most medical conditions. Only end-stage liver disease, biliary cirrhosis, and rare genetic transferrin variants alter %CDT.

Women tend to have higher and more-variable CDT values than do men, possibly because of variability in normal transferrin levels, anemia secondary to iron deficiency, pregnancy, use of oral contraceptives, or menopause. %CDT cutoff scores are not gender-specific, however, because percentage rather than absolute CDT is typically measured.

%CDT seems to decrease slightly as body mass index increases, suggesting a small but significant inverse relationship between weight and %CDT. Smoking seems to raise %CDT values slightly. The specifics of and reasons for these relationships are unclear.

Related resources

• Axis-Shield. www.axis-shield.com. Click on “Lab diagnostics,” then “Alcohol-related.”

Disclosure

Dr. Anton is a consultant to Axis-Shield.

Dr. Miller and Ms. Dominick report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Treating homeless mentally ill persons in a community-based setting—such as an inpatient medical or psychiatric unit, emergency department, or shelter clinic—requires special clinical adaptations. Four strategies can help achieve a successful intervention.

1. Engage patiently. Many homeless persons view the mental health care system with suspicion and apprehension. Meaningful engagement often develops slowly;¹ you could see a patient for weeks or months before he or she accepts treatment. Empathy and persuasion may be your most important therapeutic skills during initial encounters.

2. Assess needs broadly. During the initial evaluation ask about basic needs (safety, food, clothing, and emergency shelter) as well as psychiatric symptoms. Understandably, the homeless patient may place a much higher priority on food and shelter than on mental health services.²

Successful psychiatric treatment will be difficult if the person has no stable access to shelter. Make sure a workable strategy to obtain emergency, transitional, or permanent housing is in place.³ Work closely with the hospital’s social worker or the shelter’s case managers to facilitate this process.

3. Shape interventions pragmatically. To prevent the chaos of a shelter or the street from thwarting even a basic intervention:

• provide psychotropic samples rather than written prescriptions
  
• simplify dosing regimens to once-daily
  
• help the patient develop safe storage strategies for medications to prevent theft and exposure. For example, provide pill boxes or blister packs, or request that the shelter’s case manager store pills for the patient.
  

4. Retain arduously. Don’t expect perfect cooperation. Expect treatment nonadherence, lost or stolen medications, missed appointments, sporadic follow-through with other services, and inconsistency in abstaining from alcohol or other substances of abuse.

Set limits and establish consequences to keep a homeless person in treatment rather than to justify termination. For instance, if the patient repeatedly “loses” her medications, then provide just a few days’ supply at a time. This strategy encourages frequent follow-up and monitoring, which is more effective than discharging the patient for “noncompliance.”

Treating homeless mentally ill persons in a community-based setting—such as an inpatient medical or psychiatric unit, emergency department, or shelter clinic—requires special clinical adaptations. Four strategies can help achieve a successful intervention.

1. Engage patiently. Many homeless persons view the mental health care system with suspicion and apprehension. Meaningful engagement often develops slowly;¹ you could see a patient for weeks or months before he or she accepts treatment. Empathy and persuasion may be your most important therapeutic skills during initial encounters.

2. Assess needs broadly. During the initial evaluation ask about basic needs (safety, food, clothing, and emergency shelter) as well as psychiatric symptoms. Understandably, the homeless patient may place a much higher priority on food and shelter than on mental health services.²

Successful psychiatric treatment will be difficult if the person has no stable access to shelter. Make sure a workable strategy to obtain emergency, transitional, or permanent housing is in place.³ Work closely with the hospital’s social worker or the shelter’s case managers to facilitate this process.

3. Shape interventions pragmatically. To prevent the chaos of a shelter or the street from thwarting even a basic intervention:

• provide psychotropic samples rather than written prescriptions
  
• simplify dosing regimens to once-daily
  
• help the patient develop safe storage strategies for medications to prevent theft and exposure. For example, provide pill boxes or blister packs, or request that the shelter’s case manager store pills for the patient.
  

4. Retain arduously. Don’t expect perfect cooperation. Expect treatment nonadherence, lost or stolen medications, missed appointments, sporadic follow-through with other services, and inconsistency in abstaining from alcohol or other substances of abuse.

Set limits and establish consequences to keep a homeless person in treatment rather than to justify termination. For instance, if the patient repeatedly “loses” her medications, then provide just a few days’ supply at a time. This strategy encourages frequent follow-up and monitoring, which is more effective than discharging the patient for “noncompliance.”

Treating homeless mentally ill persons in a community-based setting—such as an inpatient medical or psychiatric unit, emergency department, or shelter clinic—requires special clinical adaptations. Four strategies can help achieve a successful intervention.

1. Engage patiently. Many homeless persons view the mental health care system with suspicion and apprehension. Meaningful engagement often develops slowly;¹ you could see a patient for weeks or months before he or she accepts treatment. Empathy and persuasion may be your most important therapeutic skills during initial encounters.

2. Assess needs broadly. During the initial evaluation ask about basic needs (safety, food, clothing, and emergency shelter) as well as psychiatric symptoms. Understandably, the homeless patient may place a much higher priority on food and shelter than on mental health services.²

Successful psychiatric treatment will be difficult if the person has no stable access to shelter. Make sure a workable strategy to obtain emergency, transitional, or permanent housing is in place.³ Work closely with the hospital’s social worker or the shelter’s case managers to facilitate this process.

3. Shape interventions pragmatically. To prevent the chaos of a shelter or the street from thwarting even a basic intervention:

• provide psychotropic samples rather than written prescriptions
  
• simplify dosing regimens to once-daily
  
• help the patient develop safe storage strategies for medications to prevent theft and exposure. For example, provide pill boxes or blister packs, or request that the shelter’s case manager store pills for the patient.
  

4. Retain arduously. Don’t expect perfect cooperation. Expect treatment nonadherence, lost or stolen medications, missed appointments, sporadic follow-through with other services, and inconsistency in abstaining from alcohol or other substances of abuse.

Set limits and establish consequences to keep a homeless person in treatment rather than to justify termination. For instance, if the patient repeatedly “loses” her medications, then provide just a few days’ supply at a time. This strategy encourages frequent follow-up and monitoring, which is more effective than discharging the patient for “noncompliance.”