Eric A. Storch, PhD

Note: this article is a continuation of “Obsessive-compulsive disorder: Tools for recognizing its many expressions,” in the March 2006 issue of JFP.

Evidence supports 2 forms of treatment for adults and children with obsessive-compulsive disorder (OCD): cognitive-behavioral therapy (CBT) with exposure and response prevention (E/RP), and psychopharmacologic treatment with serotonin reuptake inhibitors (SRIs).

OCD Expert Consensus Guidelines strongly recommend exposure-based CBT, alone or with pharmacotherapy, as the first-line treatment.¹ However, approximately 25% of persons with OCD wish not to participate in CBT for varying reasons (eg, limited insight, difficulty engaging in exposures), thus making medication alone the initial choice of treatment. In many cases, thankfully, patients whose symptoms decrease with medication become willing to participate in CBT.

Cognitive-behavioral therapy the preferred route

A large database supports the efficacy of CBT with E/RP in treating OCD. Methodologically rigorous controlled trials of CBT in adults and children have reported success rates reaching 85% (SOR: A).^2,3 One qualifier of success: though most patients respond positively to CBT, symptoms often remain and true cure or complete remission is often not possible.

CBT is unlike other psychotherapies. Unfortunately, the number of qualified mental health professionals trained in CBT for OCD is limited,⁴ as is general knowledge about this approach. The Obsessive-Compulsive Foundation estimates that 5 million Americans with OCD lack access to behavioral therapy.⁵ Many of the patients we see in our clinic have participated in psychodynamic or traditional “talk therapies” that are supported by little evidence. Such approaches have a strength of recommendation (SOR) of C. As a result, many afflicted individuals receive only partial treatment that consists of either non-CBT psychotherapy or medication.

Preparing the way for your patient

Before referring a patient for CBT, ask about the practitioner’s level of training (PhD or PsyD are preferable), theoretical approach (cognitive behavioral vs others, such as psychodynamic or humanistic), and experience in working with OCD patients. Perhaps the most important question to ask a clinician is, “Will you expose the patient to situations that provoke rituals while having him/her refrain from engaging in them?”

What your patients can expect. CBT is a form of psychological treatment explicitly based on learning and cognitive principles. Twelve to 16 sessions are typical, though the function of each individual will determine the duration of treatment.² Treatment may be stopped if significant symptom reduction has lasted for at least 4 consecutive weeks. Thereafter, periodic booster sessions are helpful to maintain gains and prevent relapse.¹

The 3 central aspects of CBT therapy for OCD:

• Exposure—placing the patient in situations that elicit anxiety related to their obsessions
• Response prevention—deterring the ritualistic or compulsive behaviors that may serve to reduce or avoid anxiety
• Cognitive therapy—training the patient to identify and reframe anxiety-provoking cognitions.

Exposure—very simply, having the patient face their fear—reduces anxiety responses.

Response prevention involves encouraging the patient to refrain from engaging in repetitive, time-consuming compulsions. This component is based on the notion that rituals serve to reduce anxiety and are thus reinforcing. Naturally, E/RP is quite anxiety-provoking for patients. As a result, it may be useful to inform them that feared situations will be approached in a hierarchical manner, starting with easier items before moving to more difficult ones. Successful completion of E/RP tasks teaches patients that the feared consequences of not ritualizing are not going to occur.

Cognitive therapy takes into account that patients with OCD have characteristic thoughts believed to contribute to the development and maintenance of their condition. Specifically, common themes within this population include distorted appraisals of risk (eg, “The chance of burning the house down with an extinguished cigarette is 25%”), an inflated sense of responsibility for harm (eg, “If I do not touch this rock, my mother will get cancer”), and pathologic levels of self-doubt (eg, “I know the odds of contracting HIV from using a public toilet are slim, but I can’t be sure I will not”). OCD in adults has also been related to the concept of thought–action fusion, in which negative thoughts and actions are seen as synonymous.⁶ Such maladaptive cognitive processes often motivate compulsive behavior and make patients with OCD less able to cope with negative thoughts.⁷ The cognitive component of CBT addresses these issues and teaches patients ways to mend their thinking.

Enlist the family. Finally, family involvement is often central to the success of CBT. Family members may accommodate the patient’s symptoms by facilitating avoidance, assisting with ritualistic behaviors, or inadvertently facilitating the development of the disorder by participating in rituals (eg, providing reassurance, allowing compulsive avoidance of feared stimuli, and tolerating delays associated with ritual completion). Given this, CBT often includes the patient’s spouse, parents, and significant others.

Pharmacotherapy

Malfunction in the serotonin neurotransmitter system is thought to be the physiologic basis of OCD.^8,9 More specifically, OCD patients are believed to have a lower level of serotonin in neural synapses than healthy persons. Given this, seretonergic agents, such as clomipramine (Anafranil), citalopram (Celexa), fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and fluvoxamine (Luvox) have been used extensively to treat OCD in both adults and youths (SOR: A). The Food and Drug Administration (FDA) has approved only clomipramine, fluoxetine, fluvoxamine, and sertraline for use in youth. Each receives an SOR of A.

Clomipramine: once first choice, now a backup

Until recently, clomipramine—a tricyclic antidepressant—was the most widely prescribed medication for OCD, given its record of providing the greatest and most reliable symptom reduction.¹⁰ The efficacy of clomipramine, which has strong seretonergic properties, has not been replicated with other tricyclic antidepressants (eg, desipramine [Norpramin, Pertofrane]) that more directly target other neurotransmitter systems (serotonin, norepinephrine, and dopamine).¹¹ However, clomipramine, like other tricyclic antidepressants, can cause tachycardia, prolongation of QT interval, and other unpleasant side effects (eg, orthostatic hypotension, constipation, and dry mouth are common). As a result, its use is indicated in cases where the patient does not respond to alternative medications.

SSRIs now favored

Given clomipramine’s side effects, selective serotonin reuptake inhibitors (SSRIs), a class of SRIs, have emerged as the first-line medication.¹² For patients who need medication, first consider prescribing an SSRI first.

SSRIs, however, are not without side effects. During the initial phase of treatment, nausea, exacerbations of anxiety, jitteriness, and insomnia are experienced by approximately 35% of patients and may persist over the duration of treatment. These side effects may be limited by slow-dose titration. With fluoxetine, for example, start at 20 mg and gradually increase the dose over several weeks to the usual target dose of 40 to 60 mg.

Some patients require even lower initial doses and more prolonged titration. Extended SSRI treatment has been linked to sexual dysfunction, headache, asthenia, and sweating in 25% to 35% of patients.¹³

Multiple large-scale controlled trials have demonstrated the efficacy and tolerability of SSRIs for adults and youths.^13,14 About 40% to 55% of patients generally report significant symptom reduction after 12 weeks. However, typical symptom reduction in clinical practice averages only 20% to 50%, and many patients experience residual symptoms after treatment has stopped.

Course of pharmacotherapy

SSRIs should be gradually titrated. The TABLE displays dosing of commonly used SSRIs in adults with OCD. A 12-week trial of an adequate dosage is the standard of care before considering alternative therapies.⁹ Initial response to medications may take 6 to 8 weeks, although the maximal response may take up to 20 weeks. Continue medications for 1 year after achieving a therapeutic response and slowly taper thereafter. Evidence suggests that ongoing CBT may be one method to prevent relapse when discontinuing medication.¹⁵ Most patients do not fully remit on medication treatment alone, and as many as 60% do not have a substantial reduction of symptoms.¹⁶

TABLE
SRI dosing guidelines recommended by the Expert Consensus Panel (1997)

For cost-effectiveness, CBT still comes out on top

It is suggested that patients continue medication consistently for 2 years before deciding to stop.⁹ Medication would therefore be expected to cost more over the long-term than CBT, given the time-limited nature and durability of the latter.³ To date, several trials have examined the relative efficacy of pharmacotherapy alone versus its combination with CBT. In general, results suggest that CBT alone or in combination with pharmacotherapy (an SRI) is the treatment of choice.^1,17

CBT plus medication often the better way to go

Given that many patients do not respond adequately to medication alone, augmentation strategies are often necessary. As CBT is considered the most effective approach, this therapy should always be used, particularly when a patient has proven refractory with pharmacological approaches. In cases that are unresponsive to multiple SSRIs and CBT, consider such second-line pharmacological treatments as serotonergic or dopaminergic agents, or adding a second first-line agent.¹³

Dopaminergic augmentation with drugs such as risperidone (Risperdal) or haloperidol (Haldol), and olanzapine (Zyprexa) have been fairly extensively studied. This approach, which consists of adding a medication that affects the dopaminergic system to the ongoing SSRI, has been well-supported.¹⁸ However, it is unclear as to how long to continue treatment as many patients relapse upon discontinuation and the antipsychotics are linked to undesirable side effects such as sedation, weight gain, or (particularly with higher doses of risperidone) extrapyramidal effects.

Strategies for adding a second serotonergic medication include switching to a new agent or adding another. Indeed, many patients with an inadequate response to one SSRI may have a favorable response to another.¹⁰

Prognosis

Left untreated, the course of obsessive-compulsive disorder is chronic and unremitting, with symptoms generally fluctuating over time due to stress-induced exacerbations of symptoms.¹⁹ Children with this disorder remain at higher risk for other psychiatric problems into adulthood,^20,21 and adults frequently display additional symptoms as well. Comorbidity with Major Depressive Disorder is particularly common in both children and adults, as are ADHD and other anxiety, mood, and tic disorders.^22-24 Symptoms also disrupt family, social, academic, and occupational functioning.^25-27

Accurate diagnosis of OCD and the identification of a qualified treatment provider remain the 2 major obstacles to treatment of OCD. In one study, the average delay between onset of symptoms and provision of appropriate treatment was 17 years.²⁷ However, once appropriate treatment begins, prognosis for patients with OCD is positive. One meta-analysis demonstrated significant long-term improvement (range, 1–15 years) in pediatric patients receiving any treatment (ie, pharmacological, psychological, or combined) for OCD.²⁸ Other studies have demonstrated that medication generally accounts for significant symptom reduction compared with baseline levels,^14,15 and 57% to 64% of pediatric patients exhibit no symptoms or subclinical levels of symptoms at follow-up.^29,30 Studies of adults have also demonstrated significant symptom reduction,¹² with about 50% of patients responding to medication.³¹ In addition, numerous studies have demonstrated that CBT is as effective or more effective than pharmacotherapy alone for both children and adults.^12,15,31

As noted previously, upwards of 85% of patients improve significantly with CBT.^3,31 Thus, CBT alone or combined with medication has the best prognosis for children and adults.

CORRESPONDENCE
Eric A. Storch, PhD, Department of Psychiatry, University of Florida, Box 100234, Gainesville, FL 32610. E-mail: [email protected]

Note: this article is a continuation of “Obsessive-compulsive disorder: Tools for recognizing its many expressions,” in the March 2006 issue of JFP.

Evidence supports 2 forms of treatment for adults and children with obsessive-compulsive disorder (OCD): cognitive-behavioral therapy (CBT) with exposure and response prevention (E/RP), and psychopharmacologic treatment with serotonin reuptake inhibitors (SRIs).

OCD Expert Consensus Guidelines strongly recommend exposure-based CBT, alone or with pharmacotherapy, as the first-line treatment.¹ However, approximately 25% of persons with OCD wish not to participate in CBT for varying reasons (eg, limited insight, difficulty engaging in exposures), thus making medication alone the initial choice of treatment. In many cases, thankfully, patients whose symptoms decrease with medication become willing to participate in CBT.

Cognitive-behavioral therapy the preferred route

A large database supports the efficacy of CBT with E/RP in treating OCD. Methodologically rigorous controlled trials of CBT in adults and children have reported success rates reaching 85% (SOR: A).^2,3 One qualifier of success: though most patients respond positively to CBT, symptoms often remain and true cure or complete remission is often not possible.

CBT is unlike other psychotherapies. Unfortunately, the number of qualified mental health professionals trained in CBT for OCD is limited,⁴ as is general knowledge about this approach. The Obsessive-Compulsive Foundation estimates that 5 million Americans with OCD lack access to behavioral therapy.⁵ Many of the patients we see in our clinic have participated in psychodynamic or traditional “talk therapies” that are supported by little evidence. Such approaches have a strength of recommendation (SOR) of C. As a result, many afflicted individuals receive only partial treatment that consists of either non-CBT psychotherapy or medication.

Preparing the way for your patient

Before referring a patient for CBT, ask about the practitioner’s level of training (PhD or PsyD are preferable), theoretical approach (cognitive behavioral vs others, such as psychodynamic or humanistic), and experience in working with OCD patients. Perhaps the most important question to ask a clinician is, “Will you expose the patient to situations that provoke rituals while having him/her refrain from engaging in them?”

What your patients can expect. CBT is a form of psychological treatment explicitly based on learning and cognitive principles. Twelve to 16 sessions are typical, though the function of each individual will determine the duration of treatment.² Treatment may be stopped if significant symptom reduction has lasted for at least 4 consecutive weeks. Thereafter, periodic booster sessions are helpful to maintain gains and prevent relapse.¹

The 3 central aspects of CBT therapy for OCD:

• Exposure—placing the patient in situations that elicit anxiety related to their obsessions
• Response prevention—deterring the ritualistic or compulsive behaviors that may serve to reduce or avoid anxiety
• Cognitive therapy—training the patient to identify and reframe anxiety-provoking cognitions.

Exposure—very simply, having the patient face their fear—reduces anxiety responses.

Response prevention involves encouraging the patient to refrain from engaging in repetitive, time-consuming compulsions. This component is based on the notion that rituals serve to reduce anxiety and are thus reinforcing. Naturally, E/RP is quite anxiety-provoking for patients. As a result, it may be useful to inform them that feared situations will be approached in a hierarchical manner, starting with easier items before moving to more difficult ones. Successful completion of E/RP tasks teaches patients that the feared consequences of not ritualizing are not going to occur.

Cognitive therapy takes into account that patients with OCD have characteristic thoughts believed to contribute to the development and maintenance of their condition. Specifically, common themes within this population include distorted appraisals of risk (eg, “The chance of burning the house down with an extinguished cigarette is 25%”), an inflated sense of responsibility for harm (eg, “If I do not touch this rock, my mother will get cancer”), and pathologic levels of self-doubt (eg, “I know the odds of contracting HIV from using a public toilet are slim, but I can’t be sure I will not”). OCD in adults has also been related to the concept of thought–action fusion, in which negative thoughts and actions are seen as synonymous.⁶ Such maladaptive cognitive processes often motivate compulsive behavior and make patients with OCD less able to cope with negative thoughts.⁷ The cognitive component of CBT addresses these issues and teaches patients ways to mend their thinking.

Enlist the family. Finally, family involvement is often central to the success of CBT. Family members may accommodate the patient’s symptoms by facilitating avoidance, assisting with ritualistic behaviors, or inadvertently facilitating the development of the disorder by participating in rituals (eg, providing reassurance, allowing compulsive avoidance of feared stimuli, and tolerating delays associated with ritual completion). Given this, CBT often includes the patient’s spouse, parents, and significant others.

Pharmacotherapy

Malfunction in the serotonin neurotransmitter system is thought to be the physiologic basis of OCD.^8,9 More specifically, OCD patients are believed to have a lower level of serotonin in neural synapses than healthy persons. Given this, seretonergic agents, such as clomipramine (Anafranil), citalopram (Celexa), fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and fluvoxamine (Luvox) have been used extensively to treat OCD in both adults and youths (SOR: A). The Food and Drug Administration (FDA) has approved only clomipramine, fluoxetine, fluvoxamine, and sertraline for use in youth. Each receives an SOR of A.

Clomipramine: once first choice, now a backup

Until recently, clomipramine—a tricyclic antidepressant—was the most widely prescribed medication for OCD, given its record of providing the greatest and most reliable symptom reduction.¹⁰ The efficacy of clomipramine, which has strong seretonergic properties, has not been replicated with other tricyclic antidepressants (eg, desipramine [Norpramin, Pertofrane]) that more directly target other neurotransmitter systems (serotonin, norepinephrine, and dopamine).¹¹ However, clomipramine, like other tricyclic antidepressants, can cause tachycardia, prolongation of QT interval, and other unpleasant side effects (eg, orthostatic hypotension, constipation, and dry mouth are common). As a result, its use is indicated in cases where the patient does not respond to alternative medications.

SSRIs now favored

Given clomipramine’s side effects, selective serotonin reuptake inhibitors (SSRIs), a class of SRIs, have emerged as the first-line medication.¹² For patients who need medication, first consider prescribing an SSRI first.

SSRIs, however, are not without side effects. During the initial phase of treatment, nausea, exacerbations of anxiety, jitteriness, and insomnia are experienced by approximately 35% of patients and may persist over the duration of treatment. These side effects may be limited by slow-dose titration. With fluoxetine, for example, start at 20 mg and gradually increase the dose over several weeks to the usual target dose of 40 to 60 mg.

Some patients require even lower initial doses and more prolonged titration. Extended SSRI treatment has been linked to sexual dysfunction, headache, asthenia, and sweating in 25% to 35% of patients.¹³

Multiple large-scale controlled trials have demonstrated the efficacy and tolerability of SSRIs for adults and youths.^13,14 About 40% to 55% of patients generally report significant symptom reduction after 12 weeks. However, typical symptom reduction in clinical practice averages only 20% to 50%, and many patients experience residual symptoms after treatment has stopped.

Course of pharmacotherapy

SSRIs should be gradually titrated. The TABLE displays dosing of commonly used SSRIs in adults with OCD. A 12-week trial of an adequate dosage is the standard of care before considering alternative therapies.⁹ Initial response to medications may take 6 to 8 weeks, although the maximal response may take up to 20 weeks. Continue medications for 1 year after achieving a therapeutic response and slowly taper thereafter. Evidence suggests that ongoing CBT may be one method to prevent relapse when discontinuing medication.¹⁵ Most patients do not fully remit on medication treatment alone, and as many as 60% do not have a substantial reduction of symptoms.¹⁶

TABLE
SRI dosing guidelines recommended by the Expert Consensus Panel (1997)

For cost-effectiveness, CBT still comes out on top

It is suggested that patients continue medication consistently for 2 years before deciding to stop.⁹ Medication would therefore be expected to cost more over the long-term than CBT, given the time-limited nature and durability of the latter.³ To date, several trials have examined the relative efficacy of pharmacotherapy alone versus its combination with CBT. In general, results suggest that CBT alone or in combination with pharmacotherapy (an SRI) is the treatment of choice.^1,17

CBT plus medication often the better way to go

Given that many patients do not respond adequately to medication alone, augmentation strategies are often necessary. As CBT is considered the most effective approach, this therapy should always be used, particularly when a patient has proven refractory with pharmacological approaches. In cases that are unresponsive to multiple SSRIs and CBT, consider such second-line pharmacological treatments as serotonergic or dopaminergic agents, or adding a second first-line agent.¹³

Dopaminergic augmentation with drugs such as risperidone (Risperdal) or haloperidol (Haldol), and olanzapine (Zyprexa) have been fairly extensively studied. This approach, which consists of adding a medication that affects the dopaminergic system to the ongoing SSRI, has been well-supported.¹⁸ However, it is unclear as to how long to continue treatment as many patients relapse upon discontinuation and the antipsychotics are linked to undesirable side effects such as sedation, weight gain, or (particularly with higher doses of risperidone) extrapyramidal effects.

Strategies for adding a second serotonergic medication include switching to a new agent or adding another. Indeed, many patients with an inadequate response to one SSRI may have a favorable response to another.¹⁰

Prognosis

Left untreated, the course of obsessive-compulsive disorder is chronic and unremitting, with symptoms generally fluctuating over time due to stress-induced exacerbations of symptoms.¹⁹ Children with this disorder remain at higher risk for other psychiatric problems into adulthood,^20,21 and adults frequently display additional symptoms as well. Comorbidity with Major Depressive Disorder is particularly common in both children and adults, as are ADHD and other anxiety, mood, and tic disorders.^22-24 Symptoms also disrupt family, social, academic, and occupational functioning.^25-27

Accurate diagnosis of OCD and the identification of a qualified treatment provider remain the 2 major obstacles to treatment of OCD. In one study, the average delay between onset of symptoms and provision of appropriate treatment was 17 years.²⁷ However, once appropriate treatment begins, prognosis for patients with OCD is positive. One meta-analysis demonstrated significant long-term improvement (range, 1–15 years) in pediatric patients receiving any treatment (ie, pharmacological, psychological, or combined) for OCD.²⁸ Other studies have demonstrated that medication generally accounts for significant symptom reduction compared with baseline levels,^14,15 and 57% to 64% of pediatric patients exhibit no symptoms or subclinical levels of symptoms at follow-up.^29,30 Studies of adults have also demonstrated significant symptom reduction,¹² with about 50% of patients responding to medication.³¹ In addition, numerous studies have demonstrated that CBT is as effective or more effective than pharmacotherapy alone for both children and adults.^12,15,31

As noted previously, upwards of 85% of patients improve significantly with CBT.^3,31 Thus, CBT alone or combined with medication has the best prognosis for children and adults.

CORRESPONDENCE
Eric A. Storch, PhD, Department of Psychiatry, University of Florida, Box 100234, Gainesville, FL 32610. E-mail: [email protected]

Note: this article is a continuation of “Obsessive-compulsive disorder: Tools for recognizing its many expressions,” in the March 2006 issue of JFP.

Evidence supports 2 forms of treatment for adults and children with obsessive-compulsive disorder (OCD): cognitive-behavioral therapy (CBT) with exposure and response prevention (E/RP), and psychopharmacologic treatment with serotonin reuptake inhibitors (SRIs).

OCD Expert Consensus Guidelines strongly recommend exposure-based CBT, alone or with pharmacotherapy, as the first-line treatment.¹ However, approximately 25% of persons with OCD wish not to participate in CBT for varying reasons (eg, limited insight, difficulty engaging in exposures), thus making medication alone the initial choice of treatment. In many cases, thankfully, patients whose symptoms decrease with medication become willing to participate in CBT.

Cognitive-behavioral therapy the preferred route

A large database supports the efficacy of CBT with E/RP in treating OCD. Methodologically rigorous controlled trials of CBT in adults and children have reported success rates reaching 85% (SOR: A).^2,3 One qualifier of success: though most patients respond positively to CBT, symptoms often remain and true cure or complete remission is often not possible.

CBT is unlike other psychotherapies. Unfortunately, the number of qualified mental health professionals trained in CBT for OCD is limited,⁴ as is general knowledge about this approach. The Obsessive-Compulsive Foundation estimates that 5 million Americans with OCD lack access to behavioral therapy.⁵ Many of the patients we see in our clinic have participated in psychodynamic or traditional “talk therapies” that are supported by little evidence. Such approaches have a strength of recommendation (SOR) of C. As a result, many afflicted individuals receive only partial treatment that consists of either non-CBT psychotherapy or medication.

Preparing the way for your patient

Before referring a patient for CBT, ask about the practitioner’s level of training (PhD or PsyD are preferable), theoretical approach (cognitive behavioral vs others, such as psychodynamic or humanistic), and experience in working with OCD patients. Perhaps the most important question to ask a clinician is, “Will you expose the patient to situations that provoke rituals while having him/her refrain from engaging in them?”

What your patients can expect. CBT is a form of psychological treatment explicitly based on learning and cognitive principles. Twelve to 16 sessions are typical, though the function of each individual will determine the duration of treatment.² Treatment may be stopped if significant symptom reduction has lasted for at least 4 consecutive weeks. Thereafter, periodic booster sessions are helpful to maintain gains and prevent relapse.¹

The 3 central aspects of CBT therapy for OCD:

• Exposure—placing the patient in situations that elicit anxiety related to their obsessions
• Response prevention—deterring the ritualistic or compulsive behaviors that may serve to reduce or avoid anxiety
• Cognitive therapy—training the patient to identify and reframe anxiety-provoking cognitions.

Exposure—very simply, having the patient face their fear—reduces anxiety responses.

Response prevention involves encouraging the patient to refrain from engaging in repetitive, time-consuming compulsions. This component is based on the notion that rituals serve to reduce anxiety and are thus reinforcing. Naturally, E/RP is quite anxiety-provoking for patients. As a result, it may be useful to inform them that feared situations will be approached in a hierarchical manner, starting with easier items before moving to more difficult ones. Successful completion of E/RP tasks teaches patients that the feared consequences of not ritualizing are not going to occur.

Cognitive therapy takes into account that patients with OCD have characteristic thoughts believed to contribute to the development and maintenance of their condition. Specifically, common themes within this population include distorted appraisals of risk (eg, “The chance of burning the house down with an extinguished cigarette is 25%”), an inflated sense of responsibility for harm (eg, “If I do not touch this rock, my mother will get cancer”), and pathologic levels of self-doubt (eg, “I know the odds of contracting HIV from using a public toilet are slim, but I can’t be sure I will not”). OCD in adults has also been related to the concept of thought–action fusion, in which negative thoughts and actions are seen as synonymous.⁶ Such maladaptive cognitive processes often motivate compulsive behavior and make patients with OCD less able to cope with negative thoughts.⁷ The cognitive component of CBT addresses these issues and teaches patients ways to mend their thinking.

Enlist the family. Finally, family involvement is often central to the success of CBT. Family members may accommodate the patient’s symptoms by facilitating avoidance, assisting with ritualistic behaviors, or inadvertently facilitating the development of the disorder by participating in rituals (eg, providing reassurance, allowing compulsive avoidance of feared stimuli, and tolerating delays associated with ritual completion). Given this, CBT often includes the patient’s spouse, parents, and significant others.

Pharmacotherapy

Malfunction in the serotonin neurotransmitter system is thought to be the physiologic basis of OCD.^8,9 More specifically, OCD patients are believed to have a lower level of serotonin in neural synapses than healthy persons. Given this, seretonergic agents, such as clomipramine (Anafranil), citalopram (Celexa), fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and fluvoxamine (Luvox) have been used extensively to treat OCD in both adults and youths (SOR: A). The Food and Drug Administration (FDA) has approved only clomipramine, fluoxetine, fluvoxamine, and sertraline for use in youth. Each receives an SOR of A.

Clomipramine: once first choice, now a backup

Until recently, clomipramine—a tricyclic antidepressant—was the most widely prescribed medication for OCD, given its record of providing the greatest and most reliable symptom reduction.¹⁰ The efficacy of clomipramine, which has strong seretonergic properties, has not been replicated with other tricyclic antidepressants (eg, desipramine [Norpramin, Pertofrane]) that more directly target other neurotransmitter systems (serotonin, norepinephrine, and dopamine).¹¹ However, clomipramine, like other tricyclic antidepressants, can cause tachycardia, prolongation of QT interval, and other unpleasant side effects (eg, orthostatic hypotension, constipation, and dry mouth are common). As a result, its use is indicated in cases where the patient does not respond to alternative medications.

SSRIs now favored

Given clomipramine’s side effects, selective serotonin reuptake inhibitors (SSRIs), a class of SRIs, have emerged as the first-line medication.¹² For patients who need medication, first consider prescribing an SSRI first.

SSRIs, however, are not without side effects. During the initial phase of treatment, nausea, exacerbations of anxiety, jitteriness, and insomnia are experienced by approximately 35% of patients and may persist over the duration of treatment. These side effects may be limited by slow-dose titration. With fluoxetine, for example, start at 20 mg and gradually increase the dose over several weeks to the usual target dose of 40 to 60 mg.

Some patients require even lower initial doses and more prolonged titration. Extended SSRI treatment has been linked to sexual dysfunction, headache, asthenia, and sweating in 25% to 35% of patients.¹³

Multiple large-scale controlled trials have demonstrated the efficacy and tolerability of SSRIs for adults and youths.^13,14 About 40% to 55% of patients generally report significant symptom reduction after 12 weeks. However, typical symptom reduction in clinical practice averages only 20% to 50%, and many patients experience residual symptoms after treatment has stopped.

Course of pharmacotherapy

SSRIs should be gradually titrated. The TABLE displays dosing of commonly used SSRIs in adults with OCD. A 12-week trial of an adequate dosage is the standard of care before considering alternative therapies.⁹ Initial response to medications may take 6 to 8 weeks, although the maximal response may take up to 20 weeks. Continue medications for 1 year after achieving a therapeutic response and slowly taper thereafter. Evidence suggests that ongoing CBT may be one method to prevent relapse when discontinuing medication.¹⁵ Most patients do not fully remit on medication treatment alone, and as many as 60% do not have a substantial reduction of symptoms.¹⁶

TABLE
SRI dosing guidelines recommended by the Expert Consensus Panel (1997)

For cost-effectiveness, CBT still comes out on top

It is suggested that patients continue medication consistently for 2 years before deciding to stop.⁹ Medication would therefore be expected to cost more over the long-term than CBT, given the time-limited nature and durability of the latter.³ To date, several trials have examined the relative efficacy of pharmacotherapy alone versus its combination with CBT. In general, results suggest that CBT alone or in combination with pharmacotherapy (an SRI) is the treatment of choice.^1,17

CBT plus medication often the better way to go

Given that many patients do not respond adequately to medication alone, augmentation strategies are often necessary. As CBT is considered the most effective approach, this therapy should always be used, particularly when a patient has proven refractory with pharmacological approaches. In cases that are unresponsive to multiple SSRIs and CBT, consider such second-line pharmacological treatments as serotonergic or dopaminergic agents, or adding a second first-line agent.¹³

Dopaminergic augmentation with drugs such as risperidone (Risperdal) or haloperidol (Haldol), and olanzapine (Zyprexa) have been fairly extensively studied. This approach, which consists of adding a medication that affects the dopaminergic system to the ongoing SSRI, has been well-supported.¹⁸ However, it is unclear as to how long to continue treatment as many patients relapse upon discontinuation and the antipsychotics are linked to undesirable side effects such as sedation, weight gain, or (particularly with higher doses of risperidone) extrapyramidal effects.

Strategies for adding a second serotonergic medication include switching to a new agent or adding another. Indeed, many patients with an inadequate response to one SSRI may have a favorable response to another.¹⁰

Prognosis

Left untreated, the course of obsessive-compulsive disorder is chronic and unremitting, with symptoms generally fluctuating over time due to stress-induced exacerbations of symptoms.¹⁹ Children with this disorder remain at higher risk for other psychiatric problems into adulthood,^20,21 and adults frequently display additional symptoms as well. Comorbidity with Major Depressive Disorder is particularly common in both children and adults, as are ADHD and other anxiety, mood, and tic disorders.^22-24 Symptoms also disrupt family, social, academic, and occupational functioning.^25-27

Accurate diagnosis of OCD and the identification of a qualified treatment provider remain the 2 major obstacles to treatment of OCD. In one study, the average delay between onset of symptoms and provision of appropriate treatment was 17 years.²⁷ However, once appropriate treatment begins, prognosis for patients with OCD is positive. One meta-analysis demonstrated significant long-term improvement (range, 1–15 years) in pediatric patients receiving any treatment (ie, pharmacological, psychological, or combined) for OCD.²⁸ Other studies have demonstrated that medication generally accounts for significant symptom reduction compared with baseline levels,^14,15 and 57% to 64% of pediatric patients exhibit no symptoms or subclinical levels of symptoms at follow-up.^29,30 Studies of adults have also demonstrated significant symptom reduction,¹² with about 50% of patients responding to medication.³¹ In addition, numerous studies have demonstrated that CBT is as effective or more effective than pharmacotherapy alone for both children and adults.^12,15,31

As noted previously, upwards of 85% of patients improve significantly with CBT.^3,31 Thus, CBT alone or combined with medication has the best prognosis for children and adults.

CORRESPONDENCE
Eric A. Storch, PhD, Department of Psychiatry, University of Florida, Box 100234, Gainesville, FL 32610. E-mail: [email protected]

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.