Understanding Fly Biting Syndrome in Dogs

Fly biting syndrome, also known as fly snapping, is a perplexing behavior. This syndrome is characterized by sudden, seemingly unprovoked snapping or biting motions in the air as if the dog is attempting to catch an invisible fly.

Symptoms and Presentation: Dogs exhibiting fly biting syndrome often display repetitive, rapid movements of the jaw or head, accompanied by an intense focus on the air. These episodes can last for seconds to minutes and may leave owners wondering if their pet is experiencing discomfort or pain.

Possible Causes: While the exact cause of fly biting syndrome is not fully understood, it is believed to have neurological origins. Some veterinarians suggest that the behavior may be linked to partial seizures, abnormal brain activity, or even certain types of headaches. It's crucial for pet owners to consult with a veterinarian to rule out any underlying health issues.

Diagnosis and Veterinary Assessment:
Diagnosing fly biting syndrome can be challenging, as it is a clinical observation rather than a specific medical condition. Veterinary professionals may conduct thorough physical examinations, blood tests, neurological assessments, and imaging studies to rule out other potential causes for the behavior.

Treatment Options: The treatment of fly biting syndrome often depends on the underlying cause, if identified. In cases where neurological issues are suspected, medication may be prescribed to manage seizures or abnormal brain activity. Behavioral interventions such as redirecting the dog's attention during episodes may also be recommended.

Living with a Dog with Fly Biting Syndrome: Pet owners of dogs with fly biting syndrome may find it emotionally challenging to witness their dogs exhibiting this behavior. Creating a calm and supportive environment, regular veterinary check-ups, and following prescribed treatment plans can contribute to a better quality of life for both the dog and its owner. In conclusion, while fly biting syndrome remains somewhat enigmatic, the collaboration between owners and veterinary professionals is crucial for understanding and managing this behavior. Early detection, accurate diagnosis, and appropriate interventions can help ensure the well-being of affected dogs.

Not to be confused with the study subject referenced below, classic tail chasing, which is frequently bidirectional, is not caused by organic problems such as a brain tumor, local irritation, or other medical conditions, and neither is it typically an attention-seeking behavior.  The objective of this research is to evaluate and define the characteristics of tail chasing in Bull Terriers and explore the association between tail chasing and other behavioral and physical characteristics. Tail chasing is a repetitive behavior that is expressed as slow to rapid circling with the dog’s attention directed toward the tail or rapid spinning in tight circles with no apparent focus on the tail. 

Dr. Alice Moon-Fanelli, Ph.D., CAABAnimal Behavior Consultations, LLC

Dr. Alice Moon-Fanelli received her Master's (1989) and Ph.D. (1993) in Biobehavioral Sciences specializing in ethology and animal behavior genetics at the University of Connecticut. As a Certified Applied Animal Behaviorist, she is internationally known for her expertise in animal behavior and regularly advises animal owners, veterinarians, other animal professionals, the public, and students on a variety of animal behavior problems. 

Dr. Moon-Fanelli has published articles in professional journals on her research as well as pet behavior problems, presents research papers, and speaks at scientific and veterinary conferences. She is interested in the causes, treatment, and inheritance of compulsive behaviors in dogs, cats, and horses.

Nicholas H. Dodman, BVMS, DACVA, DACVBProfessor Emeritus, Tufts University

Dr. Dodman is a Diplomate of the American College of Veterinary Behaviorists and Professor, Section Head, and Program Director of the Animal Behavior Department of Clinical Sciences.  Dr. Dodman is among the world’s most noted and celebrated veterinary behaviorists.  In his 1996 book, The Dog Who Loved Too Much, Dr. Dodman, under The Obsessive/Repetitive Dog, dedicates a chapter to Spuds & Co. He writes about Bull Terrier patients who show compulsive behaviors, including tail chasing and obsessive behaviors toward toys, logs, tennis balls, and so on. Dr. Dodman states in this chapter: “This is the story of my involvement with the Bull Terrier breed. Actually, it’s not just a story; for me, it has become a quest, an obsession, almost a way of life.”

---

Tail chasing is a repetitive behavior that is expressed as slow to rapid circling with the dog’s attention directed toward the tail or rapid spinning in tight circles with no apparent focus on the tail. Within the same dog, these 2 forms of expression (slow, focused; rapid, unfocused) may be expressed interchangeably. Slow chasing focused on the tail often precedes rapid unfocused spinning bouts. In its most advanced stage, tail chasing is a debilitating and potentially life-threatening behavioral condition.

Classic tail chasing, which is frequently bidirectional, is not caused by organic problems such as a brain tumor, local irritation, or other medical conditions, and neither is it typically an attention-seeking behavior. Many dogs chase their tail when separated from their owners, and when fully engaged in the behavior, the dogs appear dissociated from their environment and resistant to any form of interruption. They are often unresponsive to their owner’s commands when in this state, many shun their owner’s attention, and some become aggressive when attempts to interrupt them are made. Bull Terriers that are punished for tail chasing will often remove themselves to a location remote from the owner to engage in the behavior. Although tail chasing occurs in a variety of breeds, it is most commonly observed in Bull Terriers and German Shepherd Dogs.1,2

The disorder has previously been attributed to opioid-mediated stereotype or a seizure-related neurologic syndrome phenomenon. 4,5 The seizure-related neurologic syndrome hypothesis suggests a putative association between tail chasing and episodic aggression, trance-like behavior, hyperactivity, sound sensitivity, and fear responses and phobias. It has also been hypothesized that this neurologic syndrome has some features in common with another disease in Bull Terriers, lethal acrodermatitis. 6 In addition to having dermatologic problems, dogs with lethal acrodermatitis may have hydrocephalus and characteristic behavioral signs, such as aggression and prolonged staring. Recent studies 2, 7–9 investigating the clinical signs, development, and response to pharmacological treatment of tail chasing in dogs support a compulsive etiology similar to human obsessive-compulsive disorder. The purpose of the study reported here was to define and evaluate characteristics of tail chasing in Bull Terriers and any association with other physical and behavioral characteristics as a preliminary step toward future investigation of the inheritance of tail chasing in Bull Terriers.

Materials and Methods— Study participants—Dog owners for the study were solicited through clients of Tufts University Cummings School of Veterinary Medicine, the Bull Terrier Club of America, Bull Terrier Welfare Foundation, local dog shows, Silverwood National Bull Terrier Specialty show, and the Bull Terrier Neurological Disorder website. Convenience sampling methods were used to increase the number of dogs included in the study. Dogs were assigned to either the affected or unaffected group on the basis of the presence or absence of tail chasing as described by owners. All dogs included in the study were examined by the owner’s local veterinarian or evaluated at Tufts University Cummings School of Veterinary Medicine. Most owners of Bull Terriers with tail-chasing behavior had contacted a veterinarian for treatment advice prior to participating in the study. Owners of dogs with daily tail-chasing behavior typically requested medication to treat the condition because of the severity and disruptive nature of the behavior. No medical conditions associated with the onset or propagation of tail chasing were reported. Owners completed a research questionnaire that was designed to identify those dogs affected with compulsive tail chasing as opposed to other conditions.

Survey— Owners of dogs with tail-chasing behavior were sent a survey designed to solicit information regarding the appearance of tail chasing, age of onset, frequency of bouts, duration of bouts, and eliciting triggers. Owners were asked to provide their best estimate for age of onset and frequency and duration of tail chasing bouts on the basis of their history of living with the dog in the home. Questions regarding various physical and behavioral conditions were also included in the survey. As new behavior patterns emerged over the 16-year duration of data gathering, 2 additional questions were added to assess the degree of interference that the dog’s tail chasing caused regarding the dog’s quality of life and the owner’s relationship with the dog. Subsequent study participants were asked to report how the amount of time the dog spent tail chasing interfered with its normal daily activities and relationship with the owner. The owner was asked to score 0 for no interference, 1 for slight interference, 2 for mild to moderate interference, 3 for definite interference that was still manageable, and 4 for interference that incapacitated every aspect of the dog’s or owner’s life. When responses were unclear, owners were contacted directly for clarification. For comparative purposes, sex and neuter status as well as behavioral data were collected for all Bull Terriers in the study regardless of whether they had tail-chasing behavior. Owner-directed aggression was assessed by having owners complete a previously published checklist indicating interactions in which their dog might challenge them, including but not limited to resource guarding, routine handling, and mild restraint. 10 Owner-directed aggression included behaviors of growling, lift lip, snapping, or biting. Episodic aggression was defined as recurrent, unprovoked attacks directed toward people, other animals, or objects in the household. The attacks are explosive, violent, sudden, and unpredictable, with little to no provocation and no typical warning signals. The behavior is out of character for the dog’s normal demeanor. An awake but peaceful dog may have a transition state, often of quite short duration, in which the eyes glaze, followed by an attack.

Statistical analysis— The survey was designed to evaluate dogs on a large set of binary random variables, among these being tail-chasing behavior (yes or no), sex (male or female), coat color (white or other color), and a list of other behavioral variables. Data were analyzed in accordance with the concept of log-linear models.11 By use of this approach, tail chasing was considered as just another observed binary random variable (i.e. tail chasing was not considered as caused by the action of other variables). The count of dogs was evaluated in cross-sectional tables to evaluate whether tail-chasing behavior is observed independent of other behaviors, sex, or coat colors. The modeled variable was thus a count, not the presence or absence of tail chasing; the count of dogs was classified by sex, coat color, tail chasing status, and all other binary behavior observations. The first step in this analysis was to estimate the correlation between all the assembled elements of the survey. Being binary characters, the polychoric correlation 12 was computed by use of a software program of the public domain.a Once computed, these correlations were used to ascertain those behaviors and characters that were most closely correlated with tail chasing. Nine such characters were found to have estimates of correlations with tail chasing, and with each other, to warrant further investigation. However, 7 behavioral variables (fly-snapping, shadow and light chasing, fly snapping and shadow chasing combined, flank sucking, owner aggression 1 interaction, owner aggression 2 interaction, and deafness) were found to have poorly estimated correlation coefficients (i.e. SEs well above 1.0) and were excluded from further analysis. The remaining 10 variables formed the basis of a series of log-linear analyses. All possible sets of 8 variables, where tail chasing was kept in each set (this being the variable of principle interest), were evaluated. This was done to balance the interest in estimating unknown effects against the preponderance of empty cells given the limited number of dogs observed across the many subclasses. The initial analyses fit all 8 variables, including models for 2 and 3-way interactions. In each setting, non-significant variables were removed and a suitable submodel was chosen through comparisons of the Akaike Information Criterion and the residual deviance. In repeating this process over the 9 subsets of variables, a subset of variables and their interactions were arrived at, which were consistently found to be associated with each other. All computations were performed with the general linear model function of the R programing language with the dependent variable of counts and a Poisson model with and without consideration of overdispersion.

Results— Data were collected on 333 Bull Terriers, 145 dogs with tail-chasing behavior, and 188 unaffected dogs; however, not all dogs had information recorded for each descriptive trait. Because some owners did not answer certain questions, the total number of dogs for every variable varied.

Sex and neuter status— A total of 169 female and 164 male Bull Terriers were included in the analysis. Reproductive status was not reported for 6 dogs; reproductive status was known for 144 dogs with tailchasing behavior and 183 unaffected dogs. Thirty-one percent (45/144) of dogs with tail-chasing behavior were neutered males, and 18% (33/183) of unaffected dogs were neutered males. Thirteen percent (19/144) of dogs with tail-chasing behavior were sexually intact females, and 23% (42/183) of unaffected dogs were sexually intact females. Thirty-one percent (44/144) of dogs with tail-chasing behavior were spayed females, and 34% (62/183) of unaffected dogs were spayed females. Twenty-five percent (36/144) of dogs with tail-chasing behavior were sexually intact males, and 25% (46/183) of unaffected dogs were sexually intact males.

Age of onset— Age of onset for tail chasing was known or confidently estimated for 61% (89/145) of dogs with tail-chasing behavior. The median age of onset was 6 months. The range of age of onset was 2 months to 6 years of age.

Frequency and duration of bouts— Frequency (daily tail chasing or less than daily tail chasing) was recorded for 109 of the 145 dogs with tail-chasing behavior. Of these 109 dogs, 74% (81/109) chased their tail daily while 26% (28/109) chased their tail less than daily. Information on the duration (< 2 minutes, 2 to 30 minutes,> 30 minutes) of tail chasing was available for 67% (97/145) of the dogs with tail-chasing behavior. The average duration of a tail-chasing bout was > 30 minutes for 28% (27/97) of the dogs. Average tail-chasing bouts ranged from 2 to 30 minutes for 29% (28/97) of the dogs. Average tail chasing bouts that lasted < 2 minutes were reported for 43% (42/97) of the dogs. For 94 dogs with tail-chasing behavior, both frequency and duration data were available for cross tabulation. Of the 74 dogs that chased their tails daily for which duration data were also available, 70% (52/74) did so for 2 to 30 minutes or> 30 minutes. By comparison, of the 20 dogs that did not chase their tails daily for which duration data were also available, only 10% (2/20) did so for 2 to 30 minutes or > 30 minutes (χ² = 23.8; P < 0.001).

Ability to interrupt— Owners of 99 dogs completed the question regarding the ease with which they could interrupt their dog’s tail-chasing behavior. Eighty-seven (88%) owners reported that they could interrupt their dog from tail chasing. However, 48% (42/87) of these owners reported that the dog would immediately or within minutes resume tail chasing, indicating that the interruption was only temporary. Thirty-four percent (30/87) of owners indicated that the dog would either not resume or resume tail chasing at a later time, suggesting that these dogs were more easily interrupted. Seventeen percent (15/87) of owners reported that whether the dog resumed tail chasing following an interruption depended on the situation. If the dog was bored or stressed at the time, it would likely resume immediately to within a few minutes. If the dog’s attention could be redirected onto another activity, the tail chasing could be successfully interrupted. Ten percent (10/99) of owners could not interrupt their dog’s tail chasing, and 2 owners (2%) did not attempt to interrupt the behavior.

Triggers— As part of the survey, owners were asked an open-ended question regarding what conditions triggered the initial onset and continued elicitation of their dog’s tail-chasing behavior. A total of 129 owners responded, but many owners listed > 1 trigger A for tail chasing, resulting in 239 reported triggers. Triggers were grouped into 9 general categories. Thirty-one percent (73/239) of triggers for tail chasing involved situations that increased the dog’s level of arousal or frustration. Examples included owner departures and returns, visitors, food, presence of other dogs, aggressive interactions with other dogs, exposure to moving cars and bicycles, being released from a crate, going outside, the owner cooking, or general excitement. New, unpredictable or restrictive environments were submitted as triggers for 18% (43/239) of dogs. This category included crate confinement, new locations, closed areas, room corners, and return to indoors. Lack of mental or physical stimulation and insufficient inter action with the owner or conspecific was listed as a trigger for 15% (35/239) of dogs. Sensitivity to sound was also cited as a trigger for tail chasing for 10% (25/239) of dogs. Specific sounds reported included loud noises, rain on the roof and windows, running water, vacuum, hair dryer, lawn mower, microwave bells, and other household beeping-type alarms. Physical conditions associated with the onset and continued elicitation of tail chasing were cited for 8% (20/239) of dogs and included first or second estrus cycle, diarrhea, defecation, flatulence, hunger, fatigue, allergies, and tail injury. Ten per cent (23/239) of owners reported no discernible trigger associated with tail chasing and viewed the behavior as spontaneous. Six percent (14/239) of owners reported that their dog chased their tail at certain times of the day or in response to other situations. A change in the dog’s social group was associated with tail chasing in 2% (4/239) of dogs. The sight of certain objects (eg, broom or bag) triggered tail chasing in 1% (2/239) of dogs. The development of tail-chasing behavior differed among individuals, varying from a gradual to a sudden onset. For some dogs, the onset of tail-chasing behavior occurred suddenly with no apparent trigger, whereas for other dogs, the onset coincided with exposure to identifiable psychological, physiologic, or environmental triggers that were interpreted as increasing anxiety or arousal levels.

Interference with dog’s quality of life and owner’s relationship with dog— Fifty-one owners responded to the question of how tail chasing interfered with their dog’s normal activities. Twenty-seven percent (14/51) of owners responded that the behavior occurred with such high frequency and duration that it was negatively affecting the dog’s ability to function to the point of incapacitating every aspect of its life. Eighteen per cent (9/51) of owners reported definite interference but that the behavior was still manageable. Sixteen percent (8/51) reported that the interference was slight (5/51) to mild to moderate (3/51). Thirty-nine percent (20/51) reported that the dog’s tail-chasing behavior posed no interference. Fifty-two dog owners responded to the question of how much the dog’s tail-chasing behavior interfered with the relationship with their dog. Twenty-five percent (13/52) of owners reported that their dog’s tail-chasing behavior posed an incapacitating interference in the relationship with their dog. Another 25% (13/52) of owners reported that the tail-chasing behavior posed a definite but manageable interference. Mild to moderate interference was reported by 8% (4/52) of owners. Twelve percent (6/52) of owners found that their dog’s tail-chasing behavior caused a slight interference in the relationship with their dog, whereas 31% (16/52) reported no interference.

Injuries— Dog owners were not specifically asked to report injuries until later in the study. Fifteen dogs incurred tail injuries as a direct result of biting the tail during tail-chasing bouts, 7 of which necessitated amputation because of the severity of the injuries. Six dogs sustained injuries to the head and tarsi in the form of abrasions and cuts from banging into walls and furniture while tail chasing. Two owners reported that their dog’s digital pads and nails were severely worn because of excessive tail chasing. Eight dogs that did not respond to treatment were euthanatized because of excessive tail chasing. Another 8 dogs were euthanized because of tail chasing in conjunction with owner-directed aggression.

Degrees of expression— On the basis of clinical impression data from owner reports regarding frequency, duration, interruptability, and degree of disruption to the dogs’ normal functioning and the owners’ relationship with the dogs, 2 subsets of tail-chasing behavior were identified that differed in degree of expression for the Bull Terrier population of this study: clinical and subclinical tail-chasing behavior. Based on differences in frequency of expression only, dogs with clinical tail-chasing behavior (81/109) were those dogs that underwent multiple tail-chasing bouts on a daily basis. They often appear dissociated from the environment and unresponsive to owner commands. These dogs were not easily interrupted from tail chasing, and many had signs of anxiety or aggression if restrained. If the owner was able to interrupt the dog from tail chasing, usually by restraint or redirection onto a preferred toy or object, the dog typically resumes immediately upon release or removal of the object. On the basis of owner reports, the duration of individual tail-chasing bouts for dogs with clinical tail-chasing behavior generally ranged from 60 seconds to > 2 hours. Dogs with clinical tail-chasing behavior often chased their tail daily, usually to the exclusion of other normal activities, with tail-chasing behavior occupying an owner-estimated 30% to 80% of the dog’s daily time budget. The behavior was disruptive for both the dog and owner and in many instances was viewed by the owner as incapacitating or definitely interfering with the dog’s normal functioning (23/51 [45%]) and relationship with the owner (26/52 [50%]). Owners reported that the dog often chased its tail rather than interact with their human companions or other dogs and commented that their dog was no longer a good companion. These dogs were not reliably responsive to training commands and could not be exercised, as they chased their tail rather than walking on leash or chasing a ball. A few dogs were reported to continue to chase their tail while they urinated and defecated. Some dogs with clinical tail-chasing behavior mutilated their tail, sustained tail fractures while tail chasing, had weight loss (either because they chased their tail rather than eat or the excessive physical activity resulted in weight loss), had signs of exhaustion, and had abraded foot pads, all indicators of the severity of the behavior problem. By definition, dogs with subclinical tail-chasing behavior (28/109) had an apparently milder form of tail chasing that occurred typically 1 or 2 times/wk or 1 or 2 times/mo, usually in response to specific, predictable stimuli. The episodes were comparatively short in duration, usually < 3 minutes, and were easily interrupted by owners via distraction techniques. These dogs did not appear dissociated from their environment, responded to owner commands while tail chasing, and did not immediately resume tail chasing once they had been interrupted. Their tail-chasing behavior was not reported to interfere with the dog’s normal functioning or its relationship with the owner. However, some dogs with subclinical tail-chasing behavior later developed clinical tail-chasing behavior in response to changes in their environment or physiologic condition.

Fear responses and phobias— A total of 60 Bull Terriers, both dogs with tail-chasing behavior (n = 36) and unaffected dogs (24), were described by owners as having phobias of common objects or situations in their environment. Some owners reported > 1 trigger for their dog’s fearful behavior. Phobias were divided into 3 categories: natural environment, social, and situational. Natural environment phobias included the following: vacuums (17/60); loud noises (8/60) including vehicles, mechanical and machinery noise, and a noise-making doll; water (9/60) including hose water, bath water, and rain; stairs (2/60); heights (1/60); thunder storms (1/60); slippery floors (5/60); mopping, sweeping, and raking (9/60); reflective surfaces (3/60); novel house hold objects in environment (5/60); common household objects out of place (5/60); moving or stationary automobiles (2/60); fear of own shadow (1/60); fear of outdoors in daytime (1/60); steel doors (2/60); and doorways (1/60). Four dogs had social phobias in the presence of people dressed in white (1/60), strangers (1/60), people speaking loudly (1/60), and any human contact (1/60). Ten dogs had situational phobias involving the veterinarian’s office (3/60), grooming shop (1/60), pet store (1/60), show ring (1/60), elevators (1/60), crates (1/60), walks (1/60), and being away from home (1/60).

Owner-directed aggression— From the total of 333 dogs, 14 dogs with tail-chasing behavior expressed owner-directed aggression in ≥ 5 types of interactions with owners. Five unaffected dogs expressed owner directed aggression in ≥ 5 situations.

Episodic aggression— Twenty-two dogs had episodic aggression. Sixteen dogs with episodic aggression were dogs with tail-chasing behavior, and 6 were unaffected dogs. Ninety-five percent (20/21) of dogs with episodic aggression (not observed for 1 dog with episodic aggression) went directly from a sleep state to an attack state. All episodes were < 60 seconds in duration as described by owners. Forty-one percent (9/22) of owners also marked situations or interactions on the owner-directed aggression checklist that resulted in aggression. In all 9 instances, aggression was reported to be triggered by only 1 or 2 specific interactions.

Association of tail chasing with other variables— For determination of what physical and behavioral characteristics Table 1—Polychoric correlation values (above the diagonal [bolded 1.000 values]) and their SEs (below the diagonal) among behavioral and explanatory characteristics in 333 Bull Terriers (145 dogs with tail-chasing behavior and 188 unaffected dogs).were correlated with tail chasing, 10 variables were evaluated (Table 1). Correlations (and their associated SEs) among the 10 variables were considered in the analysis. Increased risk for developing tail chasing was not associated with coat color; dogs with white or other color coats appeared at equal risk. A history of tonic-clonic seizures, deafness, or skin allergies also was not associated with increased risk of developing tail chasing, and neither was a history of shadow chasing, fly snapping, flank sucking, or noise sensitivity. However, on the basis of polychoric correlations, several behaviors were aggregated (Table 1). Tail chasing occurred frequently with owner-directed aggression and episodic aggression (polychoric correlations of 0.377 and 0.374, respectively). Similarly, the behavior of noise sensitivity occurred frequently with episodic aggression (polychoric correlation of 0.644). A log-linear model including terms for tail chasing, episodic aggression, trance-like behavior, phobia, sex, and owner-directed aggression (≥ 5 types of interactions), along with all possible 2-way interactions, was developed (Table 2); this model captured those variables that provided the best fit to the observed counts. Not presented is the model with all possible 3-way interactions, none of which proved to be significantly different from zero, a result that was repeated across all models and submodels evaluated. Other submodels not presented included selected 3-way interactions; however, at no time were any of these terms significantly different from zero. Episodic aggression and trance-like behavior, along with sex, had significant interactions with tail chasing (Table 2). There was an 8% increase in tail-chasing males (exp 0.078 = 1.081). Positive parameter estimate for the Poisson model demonstrates that the observed frequency of male dogs that chase their tail, as well as male dogs that have had either episodic aggression or trance-like behavior, is more common than can be explained by a model of independent occurrence of these characteristics (ie, parameter estimates of 0.078, 0.620, and 0.883 vs –1.189, –2.871, and –3.493, respectively). In fact, the Akaike in formation criterion for the model with only main effects of tail chasing, episodic aggression, trance-like behavior, phobia, sex, and owner-directed aggression was 200.82, whereas the Akaike information criterion for the log-linear model was 184.84. Accordingly, the log-linear model provided a better explanation for the observed counts of these traits than that of an independent (ie, no interaction Table 2—Parameter estimates and their SEs for the log-linear model without consideration of overdispersion including counts of tail chasing, episodic aggression, trance-like behavior, sex, owner-directed aggression, and phobia, and all possible 2-way interactions for 145 Bull Terriers with tail-chasing behavior.

Discussion
To our knowledge, the study reported here represents the largest study of tail chasing in Bull Terriers to date. Tail chasing has been documented as a form of canine compulsive disorder.2,7–9 Some of the previous assertions about this purported canine compulsive disorder were confirmed and more closely detailed in the present study, while new findings, in particular, increased male susceptibility and associations of tail chasing with episodic aggression and trance-like (staring) behaviors, were made. These conclusions were based on significant interaction terms for these behaviors with tail chasing. Interestingly, there were initial models for this study in which owner-directed aggression and phobias were found to have a significant interaction with tail chasing. However, these initial exploratory models did not include terms for episodic aggression or trance-like behavior. Accordingly, overall interpretation of the final model developed in this study suggests that although owner-directed aggression and phobias had some impact on tail chasing, trance-like behavior and episodic aggression associate more strongly with tail chasing. This general observation was also supported in the polychoric correlation values (Table 1).
Our clinical perception was that many Bull Terriers with tail-chasing behavior had mild owner-directed aggression (as distinct from violent episodic aggression), although statistical analysis indicated only a loose association. A clinical explanation for the association of tail chasing with owner-directed aggression may be that increased anxiety, frustration, or conflict associated with the performance of tail chasing or the owners’ at tempts to interrupt tail chasing lower the threshold for the dogs’ aggressive response toward their owners.
The weak association between compulsive tail chasing and phobic conditions is explicable if tail chasing compulsion, like human obsessive-compulsive disorder, is regarded as an anxiety disorder. 13 According to the diagnostic manual of the American Psychiatric Association,13 various anxiety-type disorders, including specific phobia, social phobia, and panic disorder, are comorbid with obsessive-compulsive disorder. Findings of the study reported here suggest that a similar association of tail-chasing compulsion and anxiety-type disorders exists for Bull Terriers and support the bio logical homology concept of canine and human compulsive behavior.
Although tail chasing in dogs is commonly described as a compulsive disorder or partial seizure disorder,2,4,7–9 findings of the present study lead to another possibility. Males had a slight (8%) but significantly greater risk for developing tail chasing than females (Table 2). Furthermore, tail chasing in Bull Terriers is closely associated with episodic aggression and trance like behavior. In terms of the cluster of clinical signs and manifestations of tail chasing, it is speculated that this syndrome in Bull Terriers may have features in common with autism in humans. Autism is also more common in males, is associated with explosive aggression, trance-like staring, and involves repetitive movements and self-injurious behavior.14–16 In addition, autism is characterized by autonomy, impaired social interactions, and obsession with objects.16–18 Many owners of Bull Terriers with tail-chasing behavior describe their dogs as asocial, somewhat withdrawn, and abnormally preoccupied with objects, such as balls or sticks. In deed, many owners use objects to redirect their dog from tail chasing, and the dog responds to the distraction with similar intensity.
A final possible explanation for the relationship be tween tail chasing, trance-like behavior, and episodic aggression is that all stem from underlying complex partial seizures. Bull Terriers with tail-chasing behavior have been shown to have epileptiform activity on electroencephalographic recordings.4 Furthermore, violent episodic aggression in dogs has previously been described as a seizure-related problem,19,20 and trance like behavior may represent a form of partial seizure in which consciousness is altered but not lost. It is note worthy that epileptic seizures are reported in 4% to 32% of humans with autism.21,22
The present study provides detailed phenotypic and developmental information about tail chasing in dogs and illustrates some intriguing parallels with human obsessive-compulsive disorder and possibly autism. Compulsions are typically time-consuming in clinical tail chasing and obsessive-compulsive disorder, and the behavior seems to be performed in response to and in order to alleviate stress. If a dog with tail-chasing behavior or a human with obsessive-compulsive disorder is physically prevented from engaging in a compulsion, the result is mounting anxiety or tension. 13 Repeating actions in an excessive or unreasonable manner is a way that obsessive-compulsive disorder presents in humans and is the primary manifestation of tail chasing in dogs.7 In addition, the onset of tail chasing typically occurs in young adulthood shortly before or just after puberty. Early-life onset is also a feature of both obsessive-compulsive disorder and autism in humans.23,24
As with obsessive-compulsive disorder, a familial pattern of expression of tail chasing has been described.7 Obsessive-compulsive disorder and tail chasing affect so-called occupational or normal daily functioning and, as shown in this study, have a detrimental effect on social activities and relationships with others. Both disorders can be disruptive to overall functioning and may lead to self-injury. Furthermore, there is comorbidity between tail chasing and various phobias, as occurs in obsessive-compulsive disorder. That said, over 10% of autistic children have noise phobias and clinically diagnosable problems of an anxiety-related disorder, and in addition, autism is familial in expression, with an increased risk among siblings.24 Dogs with tail-chasing behavior seem to be of an anxious disposition and have been shown to respond to the same types of medications.2,25 Although there are many parallels between canine compulsive tail chasing and human obsessive compulsive disorder, if tail chasing in Bull Terriers is more closely related to autism, a new channel of translational research could be pursued relative to this common and extremely debilitating condition.

References-
1. Blackshaw JK, Sutton RH, Boyhan MA. Tail chasing or circling behavior in dogs. Canine Pract 1994;19(3):7–11.
2. Moon-Fanelli AA, Dodman NH. Description and development of compulsive tail chasing in terriers and response to clomipramine treatment. J Am Vet Med Assoc 1998;212:1252–1257.
3. Brown SA, Crowell-Davis S, Malcolm T, et al. Naloxone responsive compulsive tail chasing in a dog. J Am Vet Med Assoc 1987;190:884–886.
4. Dodman NH, Knowles KE, Shuster L, et al. Behavioral changes associated with suspected complex partial seizures in Bull Terriers. J Am Vet Med Assoc 1996;208:688–691.
5. Dodman NH, Bronson R, Gliatto J. Tail chasing in a Bull Terrier. J Am Vet Med Assoc 1993;202:758–760.
6. Uchida Y, Moon-Fanelli AA, Dodman NH, et al. Serum concentrations of zinc and copper in Bull Terriers with lethal acrodermatitis and tail-chasing behavior. Am J Vet Res 1997;58:808–810.
7. Dodman NH, Moon-Fanelli AA, Mertens PA. Veterinary models of OCD. In: Hollander E, Stein DJ, eds. Obsessive-compulsive disorders: diagnosis, etiology, treatment. New York: Marcel Dekker Inc, 1997;99–143.
8. Luescher A. Diagnosis and management of compulsive disorders in dogs and cats. ClinTech Small Anim Pract 2004;19:233–239.
9. Overall KL, Dunham AE. Clinical features and outcome in dogs and cats with obsessive-compulsive disorder: 126 cases (1989– 2000). J Am Vet Med Assoc 2002;221:1445–1452.
10. Dodman NH, Smith A, Holmes D. Comparison of the efficacy of re mote consultations and personal consultations for the treatment of dogs which are aggressive towards their owners. Vet Rec 2005;156:168–170.
11. McCullagh P, Nelder JA. Generalized linear models. 2nd ed. Lon don: Chapman & Hall, 1989.
12. Olsson U. Maximum likelihood estimation of the polychoric correlation coefficient. Psychometrika 1979;44:443–460.
13. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1995.
14. Bodfish JW, Symons FJ, Parker DE, et al. Varieties of repetitive behavior in autism: comparisons to mental retardation. J Autism Dev Disord 2000;30:237–243.
15. Parikh MS, Kolevzon A, Hollander E. Psychopharmacology of aggression in children and adolescents with autism: a critical re SM view of efficacy and tolerability. J Child Adolesc Psychopharmacol A 2008;18:157–178. LAL
16. Stone JL, Merriman B, Cantor RM, et al. Evidence for sex-specific risk VAIN alleles in autism spectrum disorder. Am J Hum Genet 2004;75:1117– ANIM 1123.A
17. Williams E, Costall A, Reddy V. Children with autism experi LSence problems with both objects and people. J Autism Dev Dis / ord 1999;29:367–378.
18. Kim JA, Szatmari P, Bryson SE et al. The prevalence of anxiety and mood problems among children with autism and Asperger syndrome. Autism 2000;4:117–132.
19. Dodman NH, Miczek KA, Knowles K, et al. Phenobarbital-responsive episodic dyscontrol (rage) in dogs. J Am Vet Med Assoc 1992;201:1580–1583.
20. de Lahunta A. Nonolfactory rhinencephalon: limbic system. In: Veterinary neuroanatomy and clinical neurology. 2nd ed. Phila delphia: WB Saunders Co, 1983;318.
21. Gabis L, Pomeroy J, Andriola MR. Autism and epilepsy: cause, consequence, comorbidity or coincidence? Epilepsy Behav 2005; 7:652–656.
22. Rossi PG, Parmeggiani A, Bach V, et al. EEG features and epi lepsy in patients with autism. Brain Dev 1995;17:169–174.
23. Short AB, Schopler E. Factors relating to age of onset in autism. J Autism Dev Disord 1988;18:207–216.
24. Chabane N, Delorme R, Millet B, et al. Early-onset obsessive compulsive disorder: a subgroup with a specific clinical and familial pattern. J Child Psychol Psychiatry 2005;46:881–887.
25. Hewson CJ, Luescher UA, Parent JM, et al. Efficacy of clomipramine in the treatment of canine compulsive disorder. J Am Vet Med Assoc 1998;213:1760–1766.

The effect of food composition on the behavior of mammals has been appreciated for many years. In dogs, the link between dietary protein content, metabolism of the amino acid tryptophan, and aggressive behavior has been the subject of considerable interest and discussion. 

The purpose of the study reported here was to evaluate the effect of High Protein and Low Protein diets with or without Tryptophan supplementation on the behavior of dogs with dominance aggression, territorial aggression, and hyperactivity. We hypothesized that Low Protein diets and diets high in Tryptophan would be associated with less aggression and reduced excitability and reactivity.

Jean S. DeNapoli, DVM

Dr. Jean DeNapoli completed her DVM degree at Tufts University School of Veterinary Medicine. After a short time in private practice, she returned to Tufts to complete a Residency in Animal Behavior. She was fortunate to study with Dr. Nicholas Dodman, BVMS, Dipl. ACVA, Dipl. ACVB and benefited from cutting-edge behavioral medicine and research practiced there. 

After again spending some time in private practice as a general practitioner and animal behaviorist, Dr. DeNapoli decided to continue her pursuit of education and experience by completing a Masters Degree program in Public Health through the University of Iowa, achieving diplomat status through the College of Veterinary Preventive Medicine.

---

Effect of dietary protein content and tryptophan supplementation on dominance aggression, territorial aggression, and hyperactivity in dogs

Objective- To evaluate the effect of high and low protein diets with or without tryptophan supplementation on the behavior of dogs with dominance aggression, territorial aggression, and hyperactivity.

Design- Prospective crossover study.

Animals- 11 dogs with dominance aggression, 11 dogs with territorial aggression, and 11 dogs with hyperactivity.

Procedure- In each group, 4 diets were fed for 1 week each in random order with a transition period of not < 3 days between each diet. Two diets had low protein content (approximately 18%), and 2 diets had high protein content (approximately 30%). Two of the diets (1 low-protein and 1 high-protein) were supplemented with tryptophan. Owners scored their dog’s behavior daily by use of customized behavioral score sheets. Mean weekly values of 5 behavioral measures and serum concentrations of serotonin and tryptophan were determined at the end of each dietary period.

Results- For dominance aggression, behavioral scores were highest in dogs fed unsupplemented high-protein rations. Tryptophan-supplemented low protein diets were associated with significantly lower behavioral scores than low-protein diets without tryptophan supplements.

Conclusions and Clinical Relevance— For dogs with dominance aggression, the addition of tryptophan to high-protein diets or change to a low-protein diet may reduce aggression. For dogs with territorial aggression, tryptophan supplementation of a low-protein diet may be helpful in reducing aggression. (J Am Vet Med Assoc 2000;217:504–508)

The effect of food composition on the behavior of mammals has been appreciated for many years.1,2 In dogs, the link between dietary protein content, metabolism of the amino acid tryptophan, and aggressive behavior has been the subject of considerable interest and discussion.3 Dogs fed a low-protein (LP) diet had decreased territorial aggression in a previous study.3 Low-protein diets, in conjunction with high carbohydrate plasma ratio of the amino acid L-tryptophan (Trp) to other large neutral amino acids (LNAA), thus affecting competition between Trp and LNAA for a common blood-brain barrier transporter mechanism.4,5 Most proteins are low in Trp and rich in LNAA so that feeding a high-protein (HP) diet will reduce the Trp:LNAA, impairing the transfer of Trp across the blood-brain barrier. 6 Conversely, LP diets result in higher Trp:LNAA, thus enhancing Trp transfer to the brain.7 Because Trp is a biosynthetic precursor for the neurotransmitter serotonin,8 decreased concentration of this amino acid will lead to reduced formation of serotonin and possibly more aggressive responses to stimuli.6,9,10 As corroboratory evidence of this hypothesis, results of studies in humans indicate that diets low in Trp increase aggression, anger, and depression,11,12 whereas increased dietary Trp has a therapeutic effect in pathologically aggressive patients 13. and promotes a feeling of well-being in people with aggressive traits. 12 In support of the hypothesis regarding serotonin and aggression, dogs that are dominant and aggressive have lower mean CSF concentration of the serotonin metabolite 5-Hydroxyindoleaceticacid (5-HIAA) than non-aggressive control dogs.14 The purpose of the study reported here was to evaluate the effect of HP and LP diets with or without Trp supplementation on behavior of dogs with dominance aggression, territorial aggression, and hyperactivity. We hypothesized that LP diets and diets high in Trp would be associated with less aggression and reduced excitability and reactivity.

From the Department of Clinical Sciences, School of Veterinary Medicine, Tufts University, Grafton, MA 01536 (DeNapoli, Dodman); the Departments of Pharmacology and Experimental Therapeutics (Shuster) and Community Health (Rand), School of Medicine, Boston, MA 02111; and Hill’s Pet Nutrition Inc, Science and Technology Center, PO Box 1658, Topeka, KS 66601-1658 (Gross). The authors thank E. Caliguri, M. Marcos, and S. Sanchez for technical assistance. Address correspondence to Dr. Dodman.

Materials and Methods Study enrollment— Thirty-eight client-owned dogs of various ages, breeds, and sexes were serially enrolled in the study; 33 dogs completed the study, whereas 5 dogs did not complete the study for various reasons. All dogs were patients at Tufts University Veterinary School Behavior Clinic and the study protocol was approved by the Tufts Animal Care and Use Committee. Each dog was required to meet specific behavioral criteria for dominance aggression, hyperactivity, or territorial aggression (Appendices 1-3) and their owners were required to agree to the terms and conditions of the study and sign a consent form. Dogs were not enrolled if they were pregnant, < 5 months of age, had received psychoactive medication within 2 weeks of initiation of the study, had a physical status score of < 3 (on a 1-to-5 scale)15 or, because of their aggressive behavior, were an immediate danger to people. A full medical history, physical examination, CBC, and serum biochemical analyses were performed to screen for diseases other than behavioral abnormalities.

Table 2—Nutrient analysis of experimental diets that contained low or high concentrations of proteins and were supplemented with L-tryptophan or were not supplemented

Study design— Dogs meeting study criteria were enrolled into 1 of 3 study groups, including a dominance aggression group, a territorial aggression group, and a hyper activity group. For each group, 4 diets were fed for a 1-week period each, in random order, with a transitional period of at least 3 days between each diet. Minimum total duration of the study for each dog was 40 days. A LP diet without supple mental Trp was designated LP–Trp, whereas a LP diet with supplemental Trp was designated LP+Trp (Table 1 and 2). A HP diet without supplemental Trp was designated HP–Trp, whereas a HP diet with supplemental Trp was designated HP+Trp. Because of supplementation, the Trp:LNAA was higher in the supplemented diets, compared with the unsupplemented diets (LNAA concentration in the diets was not determined). Diets met standards of the Association of American Feed Control Officials Nutrient Profiles for Adult Dogs and were fed to provide a daily metabolizable energy intake of 1.6 X (70 kcal X body weight [kg]0.75). Thus, for a dog that weighed 10 kg (22 lb), approximate daily Trp intake was 30, 50, 42, and 67 mg/d for LP–Trp, LP+Trp, HP–Trp, and HP+Trp diets, respectively. Diets were coded numerically and by a color code. Content of each diet was unknown to the S clinicians involved in the study. Owners were instructed to M feed the study diet exclusively and offer each dog 2 meals/d; amount fed was determined on the basis of each dog’s body weight. By use of the behavioral scores (Appendices 1-3), owners scored their dogs daily for dominance aggression, territorial aggression, fearfulness, hyperactivity, and excitability.

Serotonin and Trp analyses— For measurement of / serum Trp and serotonin concentrations, venous blood samples were obtained at the end of each week of the trial while each dog was still receiving a test diet. Sampling was conducted 1 to 2 hours after a meal to minimize the effect of postprandial variations in concentration of Trp and serotonin. Blood was drawn into a polyethylene syringe and transferred to a tube containing EDTA as anticoagulant. Samples were centrifuged for 10 minutes at 500 X g, and plasma was removed, frozen immediately, and stored at –80 C (–112 F) for up to 2 months until time of analysis. For analysis, samples were thawed and proteins were removed by centrifugation for 5 minutes at 9,000 X g after addition of an internal standard (100 ∝l of 10–6M N-methylserotonin) and 100 ∝l of 0.5M perchloric acid to 0.5 ml of plasma. Aliquots of the supernatant were injected into a high-performance liquid chromatography apparatus equipped with either a 5-∝m carbon 18 reversed-phase columna and a coulometric detector or a 2-∝m carbon 18 reversed-phase columnc and an amperometric detector.16,17,d Concentrations of serotonin and Trp were calculated from peak heights, relative to an internal standard. Peak heights were adjusted relative to the internal standard and compared with a standard curve generated on the same day. To permit a direct comparison, serotonin and Trp were calculated in molar amounts. All assays were carried out in duplicate, and standard curves were run each day.

Statistical analyses— Mean values were determined for results of 5 behavioral measurements that were recorded daily by owners during each of the dietary periods. Visual examination of the behavior data revealed that assumption of normal distributions was appropriate. Because results of Trp and serotonin analyses were not normally distributed, these data were logarithmically transformed before analysis. Each variable was analyzed independently, by use of ANOVA to first test the effects of order of fed diets and then to test significance of the 2 dietary factors (protein concentration, effect of Trp supplementation) nested within experimental groups. Interaction terms were included in the initial method and removed if not significant. The least-significant differences method was used for post hoc analysis of differences between behavior groups. All analyses were performed with computer software.e Differences were considered significant at P < 0.05.

Result— Eleven dogs in each group completed the study; mean ± SD age of territorial aggressive dogs was 3.7 ± 1.7 years (range, 1.5 to 8.5 years), mean age of dominant aggressive dogs was 5.4 ± 3.7 years (range, 2.5 to 14 years), and mean age of hyperactive dogs was 3.6 ± 2.2 years (range, 1.9 to 9.1 years).

Behavior— Significant changes in behavior were not detected within any of the 3 groups for any of the dietary treatments. As expected, dogs in the dominance aggression group had significantly higher dominance scores (P = 0.002) than dogs in the other 2 groups. After correcting for this factor, each behavior was examined across behavioral groups for the entire study population as a whole.

By use of this analysis, significant differences were detected between diet groups for certain behaviors (Table 3). Dominance scores for dogs fed the HP-Trp diet were significantly higher than those of dogs fed the other 3 diets. Territoriality scores among dogs in the different behavioral groups were not significantly different. Territoriality scores were significantly higher for dogs fed the LP–Trp diet, compared with those fed the LP+Trp diet. Significant differences in fearfulness were not detected among the 3 behavioral groups or in all dogs among the 4 diets. Hyperactivity and excitability responses differed (P < 0.001) among the behavioral groups; hyperactive dogs had the highest scores, dominant aggressive dogs had intermediate scores, and territorial aggressive dogs had the lowest scores. After correcting for these differences and analyzing data from all dogs, significant differences for hyperactivity and excitability scores were not detected among the 4 diets.

Plasma Trp and serotonin concentrations— Significant differences were not detected among behavioral groups or diets for plasma tryptophan or serotonin concentrations. The natural log of the plasma tryptophan concentration (nmol/ml) for the various diets were as follows (mean ± SE): LP–Trp, 2.49 ± 0.13, LP + Trp, 2.53 ± 0.12; HP–Trp, 2.78 ± 0.12; HP+Trp, 2.66 ± 0.12; all diets (mean ± SD), 2.61 ± 0.69. The natural log of the plasma serotonin concentration (pmol/ml) for the various diets were as follows: LP–Trp, 2.78 ± 0.18; LP+Trp, 2.59 ± 0.19; HP–Trp 2.79, ± 0.19; HP+Trp, 2.72 ± 0.18; and all diets (mean ± SD) 2.70 ± 0.90.

Discussion- As a whole, results of our study supported the hypothesis being tested. The finding that Trp supplementation of the HP and LP diets of dogs with dominance and territorial aggression, respectively, induced a significant decrease in aggression scores was anticipated. Both of these Trp-supplemented diets had higher Trp:LNAA than the 2 unsupplemented diets; the high er ratio may have resulted in a greater proportion of Trp crossing the blood-brain barrier, increasing brain serotonin concentration and decreasing aggression. A factor that may have been operating with regard to the HP diets is that increased dietary protein concentration increases plasma concentrations of tyrosine and phenylalanine,18 which are both catecholamine precursors; this change could effectively reduce the threshold for aggression.19,20 Addition of Trp (as in the HP+Trp diet) should counter this effect by increasing brain serotonin concentration, thus reducing aggression. Increasing brain serotonin concentration usually decreases aggression 21,f; however, the direction of modulation of behavior induced by serotonin varies according to the animal’s social status.22 Furthermore, the behavior modifying effect induced by altering Trp concentration depends critically on circumstance. 23 Dominant animals, unlike their subordinate counterparts, may have high, possibly fluctuating, concentrations of brain serotonin,24 making stabilization of regional brain serotonin, rather than absolute changes in its concentration, more important in terms of minimizing aggression. Another important finding was that addition of Trp to a LP diet reduced territoriality scores. The LP+Trp diet had a higher Trp:LNAA that presumably resulted in increased serotonin synthesis.25 Results of an earlier study indicate that LP diets are associated with a reduction in territorial-fear aggression in dogs.3 This finding was not replicated in our study. Territoriality scores for dogs fed the LP+Trp diet were lower than those of dogs fed either of the HP diets, but differences were not significant. The lack of influence of dietary protein content or addition of Trp to the diet on the behavior of hyperactive dogs was not unexpected, because results of recent studies 23,26,27 indicate no improvement in behavior of hyperactive laboratory animals and children treated with selective serotonin reuptake inhibitors. If potent serotonin-enhancing strategies, like the use of selective serotonin reuptake inhibitors, are ineffective in changing hyperactive behavior, it is unlikely that more subtle measures such as dietary changes would induce an observable effect. Plasma concentrations of serotonin and Trp were surprisingly consistent in all phases of our study, despite different concentrations of dietary Trp. We had expected that dietary differences would cause measurable change in the plasma concentrations of these substrates; lack of such changes could indicate that the analytic method we used was inadequate. Alternatively, we may have missed peak plasma concentrations of these substrates by obtaining samples 1 to 2 hours after a meal; recent evidence indicates that peak changes in Trp concentration may not develop until 5 hours after a meal is fed.9 Correlation between plasma serotonin and Trp concentrations was expected, because these are dependent variables. It may be more meaningful to measure platelet serotonin concentration. Results of the study reported here have potential applications for treatment of behavioral problems in dogs. Low-protein or Trp-rich diets may be helpful adjuncts in the management of dominance aggression. Also, LP diets supplemented with Trp may bebeneficial in reducing territorial aggression in dogs. One caveat regarding LP diets, however, is that they should be used only under strict nutritional guidance in young, growing dogs (< 6 months of age) and in pregnant and lactating bitches.

Appendix 1— Behavioral criteria for enrollment and assessment of dominant aggressive dogs
1) Diagnosis of dominance aggression made by a behaviorist on the basis of history and clinical findings.
2) Dogs reacted aggressively to family members in 5 of 30 dominance aggression promoting situations 3 and had some aggressive behavior at least 5 d/wk.
3) Daily dominance score ranged from 0 to 10. Criterion for a score of 1: single episode of mild aggression (growls, lifts lip, or threatens). Criterion for a score of 2: several episodes of mild aggression. Criterion for a score of 3: mild aggression in many circumstances. Criterion for a score of 4: single episode of snapping. Criterion for a score of 5: several episodes of snapping. Criterion for a score of 6: snaps in many circumstances (bites without breaking skin). Criterion for a score of 7: bites without breaking skin in several circumstances. Criterion for a score of 8: bites once (bruising or breaking skin). Criteria for a score of 9: bites in several circumstances (breaking skin or bruising, lunges, or chases repeatedly), but dog can be controlled with discipline. Criteria for a score of 10: bites (breaking skin or bruising), lunges, or chases repeatedly in many circumstances; discipline escalates the aggression.

Appendix 2— 1) Diagnosis of hyperactivity made by a behaviorist on the basis of history and clinical findings.
2) Mean daily score 5 for either a hyperactivity daily assessment scale or an excitability scale. The hyperactivity scale (range, 0 to 10) was based on the number of hyperactive actions that were performed during each day. The 10 hyperactive actions were excessive pacing or circling, not remaining in sit-stay or down-stay positions when required, excessive chewing of objects or self-mutilation, being easily distracted by extraneous stimuli, impulsive behavior (not waiting), not engaging in any particular activity for an extended period (limited attention span), playing roughly, barking or whining excessively, acting in an intrusive manner, and not heeding commands. The excitability scale (range, 0 to 10) was based on assessment of the dog in 4 situations; mean values of scores recorded during the 4 situations were used. The first situation involved the dog's behavior at home during the daytime; a score of 0 was assigned if the dog spent most of this period asleep, whereas a score of 10 was assigned if the dog paced and panted continuously; scores from 1 to 9 were assigned on the basis of owner's subjective assessment of the dog's behavior between these extremes. The second situation was the dog's reaction to the doorbell or outside noise; a score of 0 was assigned if the dog had no reaction, whereas a score of 10 was assigned if the dog reacted with uncontrollable excitement; scores from 1 to 9 were assigned on the basis of owner's subjective assessment of the dog's behavior between these extremes. The third situation involved the dog's behavior during walks; a score of 0 was assigned if the dog lagged behind the owner, whereas a score of 10 was assigned if the dog was uncontrollable; scores from 1 to 9 were assigned on the basis of owner's subjective assessment of the dog's behavior between these extremes. The fourth situation involved the time required for the dog to resume calm behavior after stimulation; a score of 0 was assigned if the dog became calm immediately, whereas a score of 10 was assigned if the dog remained excited indefinitely; scores from 1to 9 were assigned on the basis of owner's subjective assessment of the dog's behavior between these extremes.
3) Hyperactive dogs also had to have dominance score 2

Appendix 3— Behavioral criteria for enrollment and f territorial aggressive dogs
1) Diagnosis of territorial aggression was made by a behaviorist on the basis of history and clinical findings.
2) Mean daily territorial aggression score 5. The territorial aggression scale ranged from 0 to 10; a score of 0 was assigned if the dog did not bark or make menacing postures or motions when strangers approached or enter the house, whereas a score of 10 was assigned if the dog was uncontrollably aggressive when a stranger approached the house (barking, growling, baring teeth, charging the door, and similar behaviors); scores from 1 to 9 were assigned on the basis of owner's subjective assessment of the dog's behavior between these extremes.
3) Mean daily fearfulness score 3. The fearfulness scale ranged from 0 to 10; a score of 0 was assigned if the dog appeared relaxed and happy under all circumstances, without signs of fearfulness at any time, whereas a score of 10 was assigned if the dog had signs of extreme fear when confronted by any strange person, situation, or experience, or if the dog constantly followed the owner from room to room and could not be left alone without risk of damaging itself or property.
4) Territorial aggressive dogs also had to have dominance score 2 and hyperactive score 2.

References— 1. Mugford RA. The influence of nutrition on canine behavior. J Small Anim Pract 1987;28:1046–1055.
2. Pitzalis G, Vania A, Monti S, et al. Nutrition and behavior in pediatrics. Minerva Pediatr 1990;42:200–214.
3. Dodman NH, Reisner I, Shuster L, et al. Effect of dietary protein content on behavior in dogs. J Am Vet Med Assoc 1996;208:376–379.
4. Fernstrom JD. Dietary effects on brain serotonin synthesis: relationship to appetite regulation. Am J Clin Nutr 1985;42(suppl 5):1072–1082.
5. Fernstrom MH, Volk EA, Fernstrom JD. In vivo inhibition of tyrosine uptake into rat retina by larger neutral but not acidic amino acids. Am J Physiol 1986;251:E393–E399.
6. Wurtman RJ. Ways that foods can affect the brain. Nutr Rev 1986;44(suppl):2–6.
7. Wurtman RJ, Fernstrom JD. Control of brain monoamine synthesis by diet and plasma amino acids. Am J Clin Nutr 1975;28:638–647.
8. Fernstrom JD. Dietary amino acids and brain function. J Am Diet Assoc 1994;94:71–77.
9. Bjork JM, Dougherty DM, Moeller FG, et al. The effects of tryptophan depletion and loading on laboratory aggression in men: time course and a food-restricted control. Psychopharmacology (Berl) 1999;142:24–30.
10. Sarwar G, Botting HG. Liquid concentrates are lower in bioavailable tryptophan than powdered infant formulas, and tryptophan supplementation of formulas increases brain tryptophan and serotonin in rats. J Nutr 1999;129:1692–1697.
11. Moeller FG, Dougherty DM, Swann AC, et al. Tryptophan depletion and aggressive responding in healthy males. Psychopharmacology (Berl) 1996;126:97–103.
12. Cleare AJ, Bond AJ. The effect of tryptophan depletion and enhancement on subjective and behavioral aggression in normal male subjects. Psychopharmacology (Berl) 1995;118:72–81. 13. Young SN, Teff KL. Tryptophan availability, 5HT synthesis, and 5HT function. Prog Neuropsychopharmacol Biol Psychiatry 1989; 13:373–379.
14. Reisner IR, Mann JJ, Stanley M, et al. Comparison of cerebrospinal fluid monoamine metabolite levels in dominant-aggressive and non-aggressive dogs. Brain Res 1996;714:57–64.
15. Bedford PGC. Protocol for general anaesthesia in small animal patients—the increased risk patient. Small Anim Anaesthesia 1991;1:1–13.
16. Anderson GM, Feibel FC, Cohen DJ. Determination of serotonin in whole blood, platelet-rich plasma, platelet-poor plasma and plasma ultrafiltrate. Life Sci 1987;40:1063–1070.
17. Koch DD, Kissinger PT. Determination of tryptophan and several of its metabolites in physical samples by reversed-phase liquid chromatography with electrochemical detection. J Chromatogr 1979;164:441–455.
18. Maher TJ, Glaeser BS, Wurtman RJ. Diurnal variations in plasma concentrations of basic and neutral amino acids and in red cell concentrations of aspartate and glutamate: effects of dietary protein intake. Am J Clin Nutr 1984;39:722–729.
19. Haller J, Makara GB, Kruk MR. Catecholaminergic involvement in the control of aggression: hormones, the peripheral sympathetic, and central noradrenergic systems. Neurosci Biobehav Rev 1998;22:85–97.
20. Stoddard SL, Bergdall VK, Townsend DW, et al. Plasma catecholamines associated with hypothalamically-elicited defense behavior. Physiol Behav 1986;36:867–873.
21. Fuller RW. The influence of fluoxetine on aggressive behavior. Neuropsychopharmacology 1996;14:77–81.
22. Edwards DH, Kravitz EA. Serotonin, social status and aggression. Curr Opin Neurobiol 1997;7:812–819.
23. Callaway CW, Wing LL, Nichols DE, et al. Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release. Psychopharmacology 1993;111:169–178.
24. Raleigh MJ, Brammer GL, McGuire MT, et al. A dominant social status facilitates the behavioral effects of serotonergic agonists. Brain Res 1985;385:274–282.
25. Yokogoshi H, Wurtman RJ. Meal composition plasma amino acid ratios: effect of various proteins or carbohydrates, and of various protein concentrations. Metabolism 1986;35:837–842.
26. Popper CW. Antidepressants in the treatment of attention deficit/hyperactivity disorder. J Clin Psychiatry 1997;58(suppl 14):14–29.
27. Halpern JM, Sharma V, Siever LJ, et al. Serotonergic function in aggressive and nonaggressive boys with attention deficit hyperactivity disorder. Am J Psychiatry 1994;151:243–248
Correction: Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy In the Results and Discussion sections of “Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy” (JAVMA, 2000; 217:200-204), the dosages were converted from mg/kg to mg/lb incorrectly. All mg/kg dosages are stated correctly; these values should then be divided by 2.2 when converting to mg/lb. For example, in the first paragraph of the Results section, it states, “Dosages of phenobarbital ranged from 1.0 mg/kg/d [2.2 mg/lb/d] to 10.9 mg/kg/d [24 mg/lb/d]”; this should read, “…1.0 mg/kg/d [0.45 mg/lb/d] to 10.9 mg/kg/d [4.9 mg/lb/d].”

The purpose of the study reported here was to identify and treat abnormal behavior including tail chasing, unprovoked aggression, and extreme irrational fear in Bull Terriers and to establish an association between behavioral signs and any electroencephalographic or anatomic evidence of brain lesions or deafness.

Nicholas H. Dodman, BVMS, DACVA, DACVBProfessor Emeritus, Tufts University

Dr. Dodman is a Diplomate of the American College of Veterinary Behaviorists and Professor, Section Head, and Program Director of the Animal Behavior Department of Clinical Sciences. 

Dr. Dodman is among the world’s most noted and celebrated veterinary behaviorists. 

In his 1996 book, The Dog Who Loved Too Much, Dr. Dodman, under The Obsessive/Repetitive Dog, dedicates a chapter to Spuds & Co. He writes about Bull Terrier patients who show compulsive behaviors, including tail chasing and obsessive behaviors toward toys, logs, tennis balls, and so on.

Dr. Dodman states in this chapter: “This is the story of my involvement with the Bull Terrier breed. Actually, it’s not just a story; for me, it has become a quest, an obsession, almost a way of life.”

Dr. Alice Moon-Fanelli, Ph.D., CAABAnimal Behavior Consultations, LLC

Dr. Alice Moon-Fanelli received her Master's (1989) and Ph.D. (1993) in Biobehavioral Sciences specializing in ethology and animal behavior genetics at the University of Connecticut. As a Certified Applied Animal Behaviorist, she is internationally known for her expertise in animal behavior and regularly advises animal owners, veterinarians, other animal professionals, the public, and students on a variety of animal behavior problems. 

Dr. Moon-Fanelli has published articles in professional journals on her research as well as pet behavior problems, presents research papers, and speaks at scientific and veterinary conferences. She is interested in the causes, treatment, and inheritance of compulsive behaviors in dogs, cats, and horses.

---

Behavioral changes associated with suspected complex partial seizures in Bull Terriers

Nicholas Howard Dodman, BVMS; Kim Ellen Knowles, DVM, MS; Louis Shuster, PhD; Alice Ann Moon-Fanelli, PhD; Amy Sue Tidwell, DVM; Carl L. Keen, PhD

Objectives— To identify and treat a range of abnormal behavior, including tail chasing, unprovoked aggression, and extreme irrational fear, in Bull Terriers and to correlate the behavioral signs with electroencephalogram (EEG) or anatomic evidence of abnormal brain geometry or deafness.

Design— Prospective clinical study.

Animals— 8 affected and 5 unaffected (control) Bull Terriers.

Procedure— All dogs were examined neurologically, including use of EEG, brainstem auditory-evoked response, and computed tomography or postmortem examination of the brain. In addition, plasma concentrations of zinc, copper, and iron, and the activity of zinc and copper-dependent enzymes (alkaline phosphatase and ceruplasmin oxidase) were measured in affected and control dogs.

Results— An abnormal EEG was found in 7 of 7 affected dogs and in none of the control dogs subjected to this examination. Seven of 8 affected dogs and 2 of 3 controls had various degrees of hydrocephalus. Metal ion and enzyme concentrations were not different between affected and control dogs. Treatment with phenobarbital was effective in 5 of 7 dogs.

Clinical Implications— Bull Terriers with compulsive tail chasing and extreme affective disorders should be regarded as neurologically disturbed, with partial seizures perhaps underlying their behavior. Treatment with anticonvulsants is a logical first step in treatment. (J Am Vet Med Assoc 1996;208:688-691)

Bull Terriers have some aberrant behavioral patterns that, although not unique, seem particularly prevalent in this breed. Patterns we have observed include tail chasing, rage, trance-like behavior, preoccupations and fears, hyperactivity, sound sensitivity, and phobias. When these patterns are expressed mildly or irregularly, owners and breeders sometimes consider them typical breed idiosyncrasies. Sometimes tail chasing or aggression becomes so severe, however, that it constitutes a life-threatening emergency.' Although excessive endorphinergic tone has been suggested as a potential cause of tail chasing and of some other aspects of Bull Terrier behavior,2 a neurologic cause may underlie tail chasing and, possibly, certain types of aggression (rage) in this breed.' This behavioral syndrome has some features in common with another disease in Bull Terriers, lethal acrodermatitis. In addition to having dermatologic problems, dogs with lethal acrodermatitis have hydro cephalus and characteristic behavioral signs, including prolonged staring and aggression."* Lethal acrodermatitis is reported to result from hereditaryzinc deficiency,4 but because affected pups have pigment dilution, simultaneous copper deficiency is possible.3 In a previous report,' the behavioral changes of lethal acrodermatitis and tail chasing/aggression in Bull Terriers were suggested to be attributable to complex par tial seizures, perhaps localized in the temporal lobe of the brain. The purpose of the study reported here was to identify and treat abnormal behavior in Bull Terriers and to establish an association between behavioral signs and any electroencephalographic or anatomic evidence of brain lesions or deafness.

Materials and Methods— Eight Bull Terriers of various ages (mean, 24 months; range, 6 months to 6 years) and of either sex (5 males and 3 females), with behavioral signs of tail chasing (6 dogs), unprovoked aggression (1 dog), or extreme fear (1 dog) were evaluated by obtaining a detailed behavioral history from the owner. The tail-chasing dogs also exhibited some ancillary behavioral signs, including aggression, hyperexcitability, trance-like staring, "fly-catching" behavior, and other types of compulsive behavior. The dog with unprovoked aggression also displayed trance-like staring and compulsive behavior, and had a focal seizure disorder that had been diagnosed by a veterinary neurologist. All 8 dogs were examined neurologically, including a clinical neurologic examination, electroencephalogram (EEG), brainstem auditory evoked response, computed tomography (CT), or post-mortem examination of the brain. The EEG was recorded under general anesthesia with isoflurane, using a standard montage and technique, as previously described.'' The brainstem auditory-evoked responses were recorded by use of a technique described by Strain etal.7 All but 1 of the affected dogs had an EEG and CT of the brain performed. In the exception, a detailed postmortem examination was performed. A test dose of naloxone was given IV to 2 of the tail-chasing dogs (dosage, 0.02 and 0.5 mg/kg of body weight, respectively) and the rate and intensity of tail chasing were assessed over the ensuing 30-minute period. A control group of 5 Bull Terriers (mean age, 62 months; range, 5 months to 7 years, 6 months; 2 males and 3 females) that did not chase their tail or have problems relating to aggression or fear was examined in a similar way. Two control dogs were described by their owners as easily excitable, 2 showed some compulsive behavior, and 2 manifested vacant staring. To test possible biochemical links between the tailchasing syndrome and lethal acrodermatitis, plasma concentrations of zinc, copper, and iron and the activity of the zinc and copper-dependent enzymes, alkaline phosphatase and ceruloplasmin oxidase, respectively, were measured in affected and control dogs. Serum cholesterol concentration also was.

measured. Serum alkaline phosphatase activity and cholesterol concentration were evaluated by use of a routine biochemical screening. Plasma zinc, copper and iron concentrations and ceruloplasmin oxidase activity were analyzed, using standard techniques."uBlood metallothionine concentration also was assessed, using a radioactive mercury-binding test.'" Data were analyzed by a two-sample t-test.

Results

All 7 affected dogs examined by electroencephalography had abnormal EEG patterns, characterized by multiple epileptiform spikes. Dominant activity in most dogs consisted of symmetric, moderate to large amplitude (20 to 100 LtV), low-frequency (2 to 8 Hz) waves (Fig 1). None of the control dogs had an ab normal EEG. Brainstem auditory-evoked responses were normal in 6 of the 7 affected dogs tested and in 3 of the 4 control dogs tested. One affected and 1 con trol dog were unilaterally deaf on the left side. The CT of the brain revealed moderate-to-severe, regional or generalized ventriculomegaly (hydroceph alus) in 6 of 7 affected dogs. The mean CT%H of affected dogs was approximately 20% (range, 13 to 44%; n = 7); whereas control dogs had a mean CT% of 13% (range, 11 to 20%; n = 3). In 1 affected dog that was not scanned, moderate-to-severe hydrocephalus was confirmed on postmortem examination. Moderate hydrocephalus was observed in 2 of 3 control dogs scanned.

Plasma zinc, copper, and iron concentrations and ceruloplasmin oxidase activity; metallothionine activity; and serum alkaline phosphatase activity and cholesterol concentration were not significantly dilferent in affected and control dogs (Table 1). Mean serum cholesterol concentration was greater than the reference range for our laboratory (110 to 314 mg/dl) in affected and control dogs. Three main types of medication (anticonvulsants, antidepressants, and anxiolytics) were prescribed for treatment of affected dogs, with varying results. Five of the 7 dogs treated with phenobarbital (mean daily dosage, 8 mg/kg; range, 2 to 20 mg/kg) had varying degrees of improvement, with mean duration of treatment of 30 weeks (range, 6 days^lo 2.5 years). The phenobarbital-responsive group comprised 4 tail-chasing dogs and 1 dog that had extreme fear and brief paroxysms of immobility (freezing postures). Three dogs, 2 of which had decreased tail chasing when treated with phenobarbital, subsequently developed severe aggression associated with bouts of tail chasing and were euthanatized. Another dog had some decrement in tail-chasing behavior early in the course of treatment, but the owner elected to euthanatize the dog for personal reasons. One tail-chasing dog that appeared to respond well to phenobarbital also had a simultaneous environmental change. Tail chasing or "fly catching" in this dog had not recurred in 1.5 years after treatment. Although sodium bromide was given concomitantly with phenobarbital in 4 dogs, it was administered for sufficient duration to assess its effects in only 2 dogs. One of these dogs failed to respond to the combination. The other had moderate improvement, which was not attributable to bromide supplementation. One of the dogs that did not respond to phenobarbital had > 75% improvement when treated with clomipramine (25 mg, PO, q 24 h). The improvement was maintained during 1 year of treatment, and the behavior had not recurred 14 months after the owners elected to stop treatment. The dog that was not treated with phenobarbital had extreme, unprovoked aggression, but not tail chasing. This dog had an estimated 95% improvement with owner-administered homeopathic treatment. The owner has continued to administer the treatment daily and the dog's behavior has remained stable for 2 years. Neither of the dogs treated with naloxone responded to that treatment. One dog did not respond to any of the treatments.

Discussion Our preliminary data suggested that some abnormal behavior in Bull Terriers may be associated with pathophysiologic change in the CNS. In particular, abnormal epileptiform activity was a consistent finding in Bull Terriers with various extremes of abnormal behavior. These behavioral patterns ranged from "fly catching" and prolonged, unfocused staring at objects to tail chasing and extreme fear or aggression. Tail chasing, circling, "fly catching," staring, and episodic aggression have already been reported to be associated with partial seizures in dogs.3 ' 61214 The present study supported this association because all 7 of the affected dogs tested had an abnormal EEG, characterized by epileptiform spiking. Although the mean age of dogs with this syndrome was 2 years, 6 of 8 dogs were peripubertal (6 to 13 months) when clinical signs first became apparent. The adult onset of the condition in the other 2 dogs was associated with social stress. From consideration of the dogs in this study, hormonal changes or stress seem to be associated with the onset of the condition. This is similar to what is known in human epilepsy in human beings, partial seizures affecting the temporal lobe of the brain (so-called temporal lobe epilepsy) cause prolonged staring and extreme mood swings involving aggression or fear, and some affected human beings even spin in circles.13 ab These signs are similar to those we observed in affected Bull Terriers. In human beings, the ictal phase of temporal lobe epilepsy is associated with episodic behavioral changes of variable duration, and the interictal period has been shown to be associated with impaired learning and altered brain concentrations of neurotransmitters.153 Moderate-to-severe hydrocephalus was a common finding in affected dogs (7/8) in our study. Blackshaw et al1 reported enlargement of cerebral ventricles in all tail-chasing Bull Terriers examined at necropsy. Although hydrocephalus may cause abnormalities of the EEG and various neurologic signs, we do not believe that hydrocephalus was the cause of the behavioral abnormalities in the dogs we studied. One of the affected dogs with an abnormal EEG did not have hydrocephalus, and 2 of the control dogs had hydrocephalus, but a normal EEG. In this study, an association between hearing status and abnormal behavior was not apparent. Plasma assays for metallic ions and other constituents did not confirm association between the behavioral syndrome and deficiency of any of those ions in affected Bull Terriers. This may have been because an association does not exist or because the number of dogs in the study was too small for demonstration of differences. Many of the plasma constituents we assayed are labile, depending on the physiologic state of the animal and blood sampling technique. Blood zinc concentration, for example, is not a good indicator of zinc deficiency in disease states, and in 1 study in dogs, values in the affected and control groups overlapped considerably.4 Serum cholesterol concentration was high in affected and control dogs in the present study. Serum cholesterol can be high for various reasons, including diet, hypothyroidism, and copper deficiency.16 In this study, the response of affected dogs to treatment with phenobarbital and bromide was not as uniform as might have been anticipated, but was what would have been expected with these somewhat refractory seizures. The response of 1 dog to the specific serotonin-reuptake inhibitor clomipramine may have been related to mood regulation. Although another affected dog failed to respond to clomipramine, the dose used was low and the treatment period was short. In addition, this latter dog did not respond to any of the other medical treatments. The positive response of 1 affected dog to a homeopathic remedy containing copper and zinc suggested that this mode of treatment should be evaluated in additional dogs with this problem. Complex partial seizures may be responsible for a spectrum of behavioral problems in Bull Terriers. These problems range from tail chasing to aggression and extreme fear. Anticonvulsants, such as phenobarbital, would be the logical first line of treatment, though serotonin-reuptake inhibitors, like clomipramine , may be worth trying if phenobarbital treatment fails.

References
1. Blackshaw )K, Sutton RH, Boyhan MA. Tail chasing or circling behavior in dogs. Canine Pract 1994;19:7-11.
2. Brown SA, Cromwell-Davis S, Malcolm T, et al. Naloxonc-responsive compulsive tail chasing in a dog. J Am Vet Med Assoc 1987;190:884-886.
3. Dodman NH, Branson R, Gliatto J. Tail chasing in a Bull Terrier. J Am Vet Med Assoc 1993;202:758-760.
4. Jezyk PI", Haskins ME, MacKay-Smith WE, et al. Lethal acrodermatitis in Bull Terriers. J Am Vet Med Assoc 1986;188:833-839.
5. Erway LC, Grider A. Zinc metabolism in lethal-milk mice. J Hered 1984;75:480-484.
6. Dodman NH, Miczek KA, Knowles K, et al. Phenobarbital responsive episodic dyscontrol (rage) in dogs. J Am Vet Med Assoc 1992;201:1580-1583.
7. Strain GM, Kearney MT, Gignac 1G, et al. Brainstem auditory-evoked potential assessment of congential deafness in Dalmations: associations with phenotypic markers. J Vet Intern Med 1992;
6:175-182.
8. Clegg MS, Keen CL, Lounandal B, Harley LS. Influence of ashing techniques on analysis of trace elements in animal tissue. Biol Trace Elem Res 1981;3:107-115.
9. Schosinsky KH, Lehmann HP, Bceler ME. Measurement of ceruloplasmin from its oxidase activity in serum by one of o-dianisidine dihydrochloride. Clin Chem 1974;20:1556-1563.
10. Patierno SR, Pellis NR, Evans RM, et al. Application of a modified 203 Hg binding assay for metallothionein. Life Sci 1983; 32:1629-1636.
11. Spaulding KA, Sharp NJH. Ultrasonographic imaging of the lateral cerebral ventricles in the dog. Vet Radiol 1990;31:59-64.
12. Breitschwerdt EB, Breazilc JW, Broadhurst JJ. Clinical and electroencephalographic findings associated with ten cases of suspected limbic epilepsy in the dog. J Am Anim Hasp Assoc 1979;15: 37-50.
13. Beaver BV. Mental lapse aggressive syndrome. J Am Anim Hosp Assoc 1980;16:937-939.
14. Carithers RW. Psychomotor episode of a poodle. Iowa State Univ Vet 1973;35:48.
15. Schacter SC. Brainstorms, epilepsy in our words. New York: Raven Press, 1993.
16. Olin KL, Walter RM, Keen CL. Copper deficiency affect selenoglutathione peroxidase and selecnodeiodinase activities and antioxidant defense in weanling rats. Am J Clin Nutr 1994;59:65

Evaluation of a single injection method, using iohexol, for estimating glomerular filtration rate in cats and dogs S. A. Brown, D. R. Finco, F. D. Boudinot, etal

Objective— To evaluate the utility of a method for estimating glomerular filtration rate (GFR) after single IV administration of iohexol.

Design— The plasma clearance of iodine (PCI), taken as the quotient of the administered dose of iodine (300 to 600 mg of PCI/kg of body weight) divided by the area under the plasma iodine concentration versus time curve determined by 4 methods (PCI,-PCI„). The results for PCI were compared with simultaneously obtained values for the urinary clearance of exogenously administered creatinine (CCr), a widely accepted method for the measurement of GFR in cats and dogs.

Animals— Cats and dogs that were renal intact (n = 5 cats; n = 1 dog) or had renal mass reduced by partial nephrectomy (n = 5 cats; n = 7 dogs).

Results— Values for PCI were closely related (R2 values ranged from 0.947 to 0.992; P < 0.0001 in all cases) to CCr. Despite this close correlation between CCr and PCI, the 95% confidence interval for the difference between PCI3 and CCr included values that exceeded 1.4 ml/min/kg, which represents 50% of the mean value for CCr in renal-intact cats.

Conclusions—Determination of PCI provided a reliable estimate of GFR in cats and dogs of this study. However, differences between 1 of the methods (PCI3) and CCr are clinically important, emphasizing the need to use more than simple linear regression analysis and correlation coefficients when attempting to validate new measurement techniques.

Clinical Relevance— The determination of PCI provided a reliable estimate of GFR in cats and dogs of this study. (Am J Vet Res 1996;57:105-110) SJJ INXHZXXNTSX, XYFYX, FSI FZYMTW UWTKNQJX KTW YMNX UZGQNHFYNTS FY: MYYUX://\\\.WJXJFWHMLFYJ.SJY/UZGQNHFYNTS/14582182

Obsessive-compulsive disorder (OCD) is a common and debilitating psychiatric condition that affects 1% to 3% of the population worldwide, making it the fourth most common psychiatric disorder. 

This study provides preliminary supportive evidence for the effectiveness of memantine as a glutamatergic augmenting agent in severe OCD.  Future randomized double-blind placebo-controlled trials are warranted.

Dr. Evelyn Stewart, MD 

Dr. Evelyn Stewart, MD is a tenured, academic-track Professor in the Department of Psychiatry, University of British Columbia, and is the founding director of the Pediatric Obsessive-Compulsive Disorder Clinic and Research Program as well as the Chair of the Child and Youth Mental Health Research at BC Children and Women’s Health Centre. She is a clinical, genetic, and neuroscience researcher, as well as a child and adolescent psychiatrist

Nicholas H. Dodman, BVMS, DACVA, DACVBProfessor Emeritus, Tufts University

Dr. Dodman is a Diplomate of the American College of Veterinary Behaviorists and Professor, Section Head, and Program Director of the Animal Behavior Department of Clinical Sciences.  Dr. Dodman is among the world’s most noted and celebrated veterinary behaviorists.  In his 1996 book, The Dog Who Loved Too Much, Dr. Dodman, under The Obsessive/Repetitive Dog, dedicates a chapter to Spuds & Co. He writes about Bull Terrier patients who show compulsive behaviors, including tail chasing and obsessive behaviors toward toys, logs, tennis balls, and so on. Dr. Dodman states in this chapter: “This is the story of my involvement with the Bull Terrier breed. Actually, it’s not just a story; for me, it has become a quest, an obsession, almost a way of life.”

---

A Single-Blinded Case-Control Study of Memantine in Severe Obsessive-Compulsive Disorder

S. Evelyn Stewart, MD,*Þþ Eric A. Jenike, BA,*Þ Dianne M. Hezel, BA,*Þ Denise Egan Stack, MA,* Nicholas H. Dodman, BVMS,§ Louis Shuster, PhD,§ and Michael A. Jenike, MD*þ

Background: Obsessive-compulsive disorder (OCD) is a common debilitating psychiatric illness that typically improves but does not remit with first-line medication and behavioral treatments. Serotonergic agents including selective serotonin reuptake inhibitors and clomipramine have provided the mainstay of OCD medication management for decades. Combined dopamine/serotonergic agents such as atypical antipsychotics are presently the only OCD-augmenting strategies proven effective via randomized controlled trials. Despite increasing evidence for a pathogenic role of glutamate in OCD, no controlled trials of glutamatergic augmenting agents have been reported.

Methods: An intent-to-treat sample included 44 subjects receiving standard treatment at the McLean/Massachusetts General Hospital Intensive Residential Treatment (IRT) program, 22 of whom also received memantine augmentation. Admission, monthly and discharge measures of OCD, depression, and psycho-social functioning were collected by raters blinded to augmentation status. Matched controls were selected based on sex, initial OCD severity, psycho-social functioning, and timing of admission. The Clinical Global Improvement Scale captured global clinical change.

Results: Mean (SD) Yale-Brown Obsessive Compulsive Scale score decreases were 7.2 (6.4) among the cases and 4.6 (5.9) among the matched controls, reflecting mean clinical improvement among the cases (27.0% decrease) but not the controls (16.5% decrease). Mean (SD) depression severity score decreases were 5.8 (9.5) among the cases and 4.7 (9.9) among the controls. Initial intrusive obsessions were significantly more severe among marked responders compared with limited response or non-response cases (4.4 vs 2.9; t = 2.15; P = 0.048).

Conclusions: This study provides preliminary supportive evidence for the effectiveness of memantine as a glutamatergic augmenting agent in severe OCD. Future randomized double-blind placebo-controlled trials are warranted.

Key Words: obsessive-compulsive disorder (OCD), memantine, glutamate, augmenting agents, anxiety disorders, treatment.

Obsessive-compulsive: Obsessive-compulsive disorder (OCD) is a common and debilitating psychiatric condition that affects 1% to 3% of the population worldwide,1 making it the fourth most common psychiatric disorder.2 First-line OCD treatments, including selective serotonin reuptake inhibitors (SSRIs), cognitive behavior therapy (CBT), and their combination, are effective in approximately 42% to 50%,3 62%, and 70% of cases, respectively.4 However, symptoms often persist and full remission is uncommon with first-line approaches.5,6 When symptoms remain severe, a medication switch or use of augmenting agents may become necessary. Switching from one SSRI to another benefits approximately 40% of OCD patients.7 Although successful trials of atypical antipsychotics have demonstrated further symptom reduction, no controlled studies of glutamatergic agents as augmenting agents for standard OCD pharmacotherapy have yet been reported. Obsessive-compulsive disorder augmenting strategies reported in randomized controlled trials to date include the atypical antipsychotics risperidone,8 quetiapine,7 and olanzapine,9 which act on serotonergic-dopaminergic systems. Open-label studies and reports have also supported use of trazodone,10,11 aripiprazole,12 topiramate,13,14 and mirtazapine15,16 in partial responders and nonresponders. Open-label trials of the glutamatergic agents riluzole,17 n-acetylcysteine,18 and memantine19,20 have emerged in recent years, but no controlled studies of these agents have yet been reported in OCD. Several lines of evidence implicate glutamatergic neuro-transmission as a putative etiologic factor in OCD.21,22 Increased glutamate levels in cerebrospinal fluid,23 in the prefrontal and orbitofrontal cortex and in the striatum,24Y26 and reversible dysfunction in the glutamate-mediated corticostriatothalamic circuit26 have been reported. Significant associations with OCD have been identified for genes including the glutamate receptor, ionotropic, N-methyl-D-aspartate 2B (GRIN2B)27; glutamate receptor, ionotropic kainite 2 (GRIK2)28 (Sampaio AS, Fagerness J, Crane J, et al. Association between GRIK2 polymorphisms and OCD: a family-based study. in press); and findings have been independently replicated for glutamate transporter (SLC1A1) genes.29Y32 Knockout mice for the striatum-expressed SAPAP3 gene, coding for a postsynaptic scaffolding protein at corticostriatal glutamatergic excitatory synapses, also developed facial lesions, repetitive grooming behaviors, and anxiety that were reversed with an SSRI and with gene replacement.33 Memantine is a glutamate receptor antagonist that has been reported to reduce OCD symptoms in case studies of treatment-resistant individuals.19,20,34,35 In this intent-to-treat, single-blinded, naturalistic case-control study, we examine the effectiveness of memantine as an augmenting agent to standard intensive residential treatment of severe OCD.

MATERIALS AND METHODS

Subjects The study population comprised 44 subjects receiving standard treatment at the McLean Hospital/Massachusetts General Hospital OCD Institute Intensive Residential Treatment (IRT) program, admitted between May 1999 and December 2007. Frequencies of other prescribed standard OCD medications among the case patients and the control subjects at trial initiation were 59.1% (n = 13 case patients) versus 72.7% (n = 16 control subjects) for SSRI or clomipramine (P = 0.34), 36.4% (n = 8 case patients) versus 27.3% (n = 6 control subjects) for benzodiazepines (P = 0.52), and 27.3% (n = 6 case patients) versus 22.7% (n = 5 control subjects) for atypical antipsychotics (P = 0.73). There were no significant differences between the case and control groups with respect to non-memantine medication dose changes, initiations or discontinuations during the memantine trial (P 9 0.05). The threshold criteria for admission to the OCDI include the presence of severe OCD-related impairment and inadequate prior response to standard treatment modalities. These criteria are established via admission package information, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) severity scores, and collateral information from family members and treating clinicians and are subsequently confirmed by OCDI psychiatrist assessments. In general, the program exclusion criteria include conditions that preclude significant engagement in IRT, such as severe mental retardation, primary psychotic illness, active substance dependence, or suicidality. The OCDI comprises intensive behavioral, medication, and milieu OCD treatment provided by a multi-disciplinary team of psychiatrists, behavior therapists, social workers, nurses and counselors, with a highly structured program that enables close monitoring of treatment adherence. All residents participate in 2 to 4 hours of CBT daily and weekly psychopharmacology assessments by OCD expert psychiatrists to monitor medication efficacy and adverse effects. More extensive details of this treatment program have been provided elsewhere.

Study Design Among consecutive patients requiring medication augmentation, 22 gave informed consent to an IRT psychiatrist (M.A.J.) for an off-label trial of the augmenting agent, memantine. To control for confounding effects of nonmedication therapeutic aspects of the OCD program, matched IRT controls were selected based on sex, Y-BOCS, and Work and Social Adjustment (WSA) scores at admission (T1 point). The most recent subject from the OCDI research database found to meet these criteria for each case was identified as the matched control. These matching criteria were preliminarily established based on previous research at this program that identified OCD severity, psycho-social functioning, and sex as predictors of IRT outcome.

Measures The following standard admission, monthly and discharge psychometric IRT program outcome measures were used in this study. Measures were administered by trained and experienced IRT staff members. The Y-BOCS is a 10-item measure rating each item between 0 (lowest severity) and 4 (highest severity). It has a high convergent validity with the National Institute of Mental Health Obsessive-Compulsive Scale (r = 0.67)38 with excellent reliability.38,39 The Y-BOCS checklist has more than 60 items organized into 2 miscellaneous categories and 13 other categories according to thematic content. The Beck Depression Inventory (BDI) is a 21-item depression severity scale with a reliability of 0.92, a construct validity correlation with the Symptom Checklist-90-Revised of 0.76, sensitivity of 100%, and specificity of 89% (using a cutoff score of 16).22,40,41 The Obsessive-Compulsive Rating scale is a questionnaire-based measure that rates the severity of OCD symptom categories between 0 and 10. This measure has good internal consistency with a Cronbach > of 0.83 for the total severity score and good convergent validity with the Y-BOCS.42 The WSA scale is a 5 item measure assessing functional impairment and quality of life, with test-retest reliability of 0.73, convergent validity with clinician interviews of 0.81 to 0.86, and increasing scores that reflect worse functional impairment.43 The Clinical Global Impression (CGI) scale provides an assessment of overall impact of treatment rated between 1 (very much improved) and 7 (very much worse). The aforementioned study instruments were administered by experienced, bachelor level IRT counselors in the IRT program who were randomly assigned to study subjects and supervised by PhD level psychologists with OCD expertise.

Analyses Data were coded from completed measures at admission, monthly intervals, and discharge and were subsequently double-entered into a database and verified. The primary study outcome measure was defined as percent change in Y-BOCS OCD severity scores between admission and discharge. For a small minority of subjects, discharge measures of OCD severity were not obtained because of causes including premature discharge from the program. When unavailable, a last observation carried forward (LOCF) approach was used to define proxy discharge scores for analyses. In those cases, the similar time point for the matched control was used as the final discharge/LOCF score for comparison in an attempt to match the cases and the controls as closely as possible on all relevant variables (given that the IRT program has multiple modalities that may potentially impact OCD severity in a time-dependent manner). Moreover, any subjects without at least 1 pre-memantine and 1 post-memantine OCD severity score were excluded from study. Secondary outcomes of interest included changes in comorbid depression severity as measured by the BDI, psycho-social functioning changes as measured by the WSA scale, and global improvement as measured by the CGI scale. Clinically significant treatment response was defined by a Y-BOCS score decrease of at least 25% (as used in previous studies10) and marked response was defined by a 50% Y-BOCS score decrease. Descriptive and comparative analyses were conducted between the case and control groups and also between the responders and the nonresponders in the entire group and in the cases alone, using t tests and W2 tests and a cutoff of P = 0.05 to indicate statistical significance.

RESULTS For the 44 matched study subjects at admission, mean (SD) scores were 26.8 (5.2) for the Y-BOCS, 18.2 (9.1) for the BDI, and 28.2 (5.3) for the WSA. The mean (SD) admission length was 62 (37.3) days, and 68.2% (n = 30) of subjects were male. There were no notable or serious adverse effects or related discontinuations of memantine. Admission and discharge (or LOCF) scores reflecting OCD severity, psycho-social functioning, and self-reported improvement were compared between the case and the control groups. There were no significant differences identified between the case and the control groups on any admission (preaugmentation) measures (P 9 0.2). The mean (SD) Y-BOCS decrease was equal to 7.2 (6.4) for the cases and 4.6 (5.9) for the controls. These data represent a clinically significant (Q25% decrease) mean improvement for the case group (27.0% decrease) but not the control group (16.5% decrease). The mean starting dose of memantine was 5 mg. The mean duration to the first dose increase was 7.6 days and the mean final memantine dose was 18.0 mg. Among the responders in both groups, those in the case group were significantly more likely to have a 50% OCD severity decrease compared with those in the control group (22.7% of the case group vs 4.5% of the control group; W2 = 4.27, P = 0.04). According to available CGI discharge (LOCF) measures (n = 31), all the case patients had at least a minimal improvement. Moreover, 35.3% (n = 6) of the case patients were very much improved[ compared with 7.1% (n = 1) of the control subjects. The likelihood of being rated as very much improved was 3.8 times higher in the case group versus the control group (P = 0.05). None of the case patients and 14.3% (n = 2) of the control subjects demonstrated worsening or no change at discharge. Clinical characteristics of the nonresponder, the responder, and the marked responder case patients are summarized in Table 1, including details of OCD symptom types, comorbidities, psycho-social functioning and other medications. No differences in OCD symptom category type were identified between the responders and the nonresponders in the overall sample or in the case group alone. Furthermore, no OCD symptom type differences were identified between the responders in the case and the controls groups (P 9 0.05). Symptom types with the highest mean (SD) severity scores (rated out of 10) among the case and the control groups included washing (6.1 [4.3]), repeating (5.9 [3.9]), and telling/asking/ confessing (5.7 [3.7]) obsessions and compulsions. Marked responders (with at least 50% OCD improvement) had significantly higher intrusive obsession scores (4.4 vs 2.9, t = 2.15, P = 0.048) versus the subjects without a marked response. Among these marked responders, the most severe subtypes were sexual obsessions (7.5 [5.0] vs 4.1 [4.2] for poorer response) and checking compulsions (6.0 [2.3] vs 5.5 [4.6] for poorer response). Depression severity was not significantly different between the case patients and the control subjects upon admission (P = 0.82) or at discharge (LOCF; P = 0.64). However, both discharge (LOCF) depression severity (t = 2.12, P = 0.04) and psycho-social functioning WSA (t = 5.9, P G 0.001) scores were significantly lower among the IRT (case and control groups) OCD responders versus the nonresponders. In examining the responder versus the nonresponder case patients only, the discharge (LOCF) WSA scores were also significantly improved among the responders (t = 5.4, P G 0.001), although the depression severity did not significantly differ (t = 1.8, P = 0.09).

DISCUSSION Results from this controlled single-blinded study demonstrate memantine as an effective augmenting agent to standard IRT treatment in severe OCD. This expands upon previous open-label trials and case reports suggesting the drug’s efficacy.19,20,34,35 A mean OCD severity improvement of at least 25%, denoting clinically significant improvement, was noted among the case patients but not the control subjects. From a clinical perspective, this finding suggests promise for the use of memantine in OCD. This medication was approved by the Food and Drug Administration in 2003. Its safety profile and patient tolerability are very good, with no known cardiotoxic, hepatotoxic, or serious adverse effects. It is not associated with physiological tolerance and is not metabolized by the cytochrome P450 system, thus increasing its ease of use in combination with other medications. Memantine has not been approved specifically for use in children, which is a concern given that OCD frequently begins in childhood. However, a recent case report of its safe, effective use in an adolescent has been published.19 Although the mean Y-BOCS score decrease among the case patients represented a clinically significant improvement, only 36.4% (n = 8) of the case patients were responders (925% Y-BOCS decrease). This suggests that the responders predominantly had greater than the minimum threshold of 25% improvement, driving the mean score change for the entire case group. As such, memantine and other glutamatergic agents may be preferentially beneficial to as of yet undefined OCD subtypes. Ideally, this study would explore response predictors for memantine and examine its effectiveness and tolerability. For example, an augmentation study of risperidone (acting on dopaminergic and serotonergic neurotransmitter systems) demonstrated response in a subsample (n = 4 of 9) of OCD patients with lower striatal metabolism and higher anterior cingulum metabolism.44 The relatively small sample size in the present study precluded a thorough examination of symptom dimensions, age of onset, or focal metabolism as potential treatment response predictors. No differences in OCD symptom types were identified between the case responders (925% Y-BOCS improvement) and the nonresponders (e25% Y-BOCS decrease; P 9 0.07), although the marked responders (950% Y-BOCS decrease) had significantly higher intrusive obsession scores (4.4 vs 2.9, t = 2.15, P = 0.048) compared with the other case patients (e50% Y-BOCS decrease). Among the marked responders, the most severe obsessions were sexual (7.5 vs 4.1 for the poorer response group) and compulsions were checking (6.0 vs 5.5). Interestingly, these symptoms and intrusive obsession symptoms are all represented in the Bisexual/ religious/aggressive/somatic/checking[ symptom dimension previously described in adult and child samples.45,46 Given the cognitive benefits of memantine in Alzheimer’s disease, it could be postulated that this agent may be preferential for use in OCD patients with prominent cognition-related obsession symptoms within this symptom dimension, rather than for those with more physical or stand-alone rituals. However, this hypothesis will require testing in future larger randomized controlled trials. Percent decrease in depression severity after IRT treatment was not significantly different between the case group (32.1%, SD 46.7) and the control group (12.8%; t = j1.1, P = 0.28). However, the depression improvement was significantly greater among the combined case-control OCD responders (45.3% BDI decrease) versus the nonresponders (1.4% BDI decrease; t = 2.99, P = 0.006). This pattern was also seen in the case-only responders (58.7%) versus the nonresponders (5.5%; t = 2.7, P = 0.02) but was not seen in the control-only responders (32.0%) versus the nonresponders (9.2%; t = 1.7, P = 0.12). Discharge (or LOCF) psycho-social functioning scores were better among the IRT responders versus the nonresponders (t Q 5.4, P G 0.001) regardless of the case-control status. This study examines in vivo effectiveness of memantine as an augmenting agent with standard IRT in complex, severely ill OCD patients with comorbidities, rather than studying efficacy in a higher functioning, comorbidity-free population. Although subjects are atypical from those included in double-blinded randomized placebo-controlled trials, this study was designed to increase generalizability of its findings to individuals with severe OCD that warrants treatment augmentation.47 From a research perspective, this study provides an additional line of converging preliminary evidence implicating the glutamate pathway as a potential target in OCD treatment. It has been well established that excess interneuronal glutamate levels may result in excitotoxicity for neurons. Memantine is a noncompetitive antagonist of glutamate receptors of the N-methyl-D-aspartate type. As such, it is a logical choice for use in moderate to severe Alzheimer disease, for which it is approved by the Food and Drug Administration. Altered glutamate receptor levels have been found in OCD-implicated brain areas,48 the OCD-associated GRIK2 glutamate receptor gene has messenger RNA that is prominent in these areas (striatum and caudate),28,49 and the OCD-associated GRIK receptor gene is known to influence glutamate-induced neuronal degeneration in the basal ganglia. Glutamate also interacts with previously implicated monoamine systems in OCD pathology (including serotonin and dopamine) in a complex manner. Glutamate agonists facilitate presynaptic synthesis and release of dopamine in the prefrontal cortex.24 Moreover, glutamate receptor antagonism leads to an enhancement of 5-HT2A receptorYmediated transmission; 5-HT2A agonism leads to reduced glutamatergic transmission24 and 5-HT receptor activation reduces the excitatory effect of glutamate on cellular activity.50 It is this interaction that is believed to contribute to some mechanisms of psychiatric symptoms.51 Given the previously reported white matter abnormalities and white matter volume decreases in OCD,52,53 it could also be hypothesized that this is a direct or indirect product of cytotoxic damage. However, such claims would be premature at present and require future study. Nonetheless, memantine has reportedly been effective in a randomized placebo-controlled study of schizophrenia, another psychiatric illness in which white matter abnormalities have been implicated.54 Limitations of this study must be acknowledged. Specifically, the cases comprise a convenience sample of individuals placed on memantine during IRT for OCD. However, all IRT participants received regular admission and monthly and discharge measures (not administered by the treating physician) such that the control subjects, and the raters were blinded to their involvement in these analyses and to medication status. The case patients were aware of their treatment with memantine, thus introducing a potential placebo effect. All the case patients and control subjects (in response to a standard offer to all new IRT patients) initially gave written consent to the anonymous release of their clinical data for research purposes. The decision to conduct matching of the cases to the controls occurred only after the discharge of all participants, such that randomization to the treatment groups did not occur. However, this does not preclude measurement bias regarding potential memantine effects. Matching variables were defined before selection of the control group. Given that this augmentation occurred in the context of IRT, which incorporates both the standard OCD medication and the CBT approaches, examining the improvement of the case patients alone would provide inadequate specificity regarding impact of memantine. Thus, careful matching inclusive of all variables found to be associated with IRT outcome was conducted in an attempt to isolate the effect of memantine. Although there was no medication matching, this factor did not previously yield significant differences in predicting IRT outcome. Despite these efforts, it is possible that some selection bias may have remained as a consequence of lack of randomization in the study design. Owing to the study approach, no weekly measures were available to accurately determine time to effect. Moreover, although the sample size had sufficient power to detect a difference between groups, the limited numbers precluded analyses to identify memantine response predictors.

CONCLUSION This single-blinded matched case-control study of standard IRT with versus without memantine in a severe OCD sample demonstrates promise for memantine as an augmenting agent. Moreover, it provides a further converging line of evidence pointing to a putative pathological role of glutamate in OCD. Future randomized controlled trials attempting to replicate these findings and to identify memantine response predictors in a larger OCD sample are warranted

AUTHOR DISCLOSURE INFORMATION Dr Evelyn Stewart has received support from the Anxiety Disorders Association of America (ADAA), the Obsessive-Compulsive Foundation (OCF), the American Academy of Child and Adolescent Psychiatry (AACAP), and a nonindustry, not-for-profit private fund. The other authors report no competing interests.

REFERENCES
1.Karno M, Golding JM, Sorenson SB, et al. The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry. 1988;45:1094Y1099.
2. Kaplan H, Sadock B. Introduction. Synopsis of Psychiatry. Baltimore, MD: Williams & Wilkins; 1998.
3. Swedo SE, Snider LA. The neurobiology and treatment of obsessive compulsive disorder. In: Nestler EJ, Charney DS, eds., Neurobiology of Mental Illness. New York, NY: Oxford University Press; 2004: 628Y638.
4. Foa EB, Liebowitz MR, Kozak MJ, et al. Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder. Am J Psychiatry. 2005;162:151Y161.
5. Ackerman DL, Greenland S. Multivariate meta-analysis of controlled drug studies for obsessive-compulsive disorder. J Clin Psychopharmacol. 2002;22:309Y317.
6. Mataix-Cols D, Rauch SL, Baer L, et al. Symptom stability in adult obsessive-compulsive disorder: data from a naturalistic two-year follow-up study. Am J Psychiatry. 2002;159:263Y268.
7. Denys D, de Geus F, van Megen HJ, et al. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry. 2004;65:1040Y1048.
8. Li X, May RS, Tolbert LC, et al. Risperidone and haloperidol augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder: a crossover study. J Clin Psychiatry. 2005;66:736Y743.
9. Bystritsky A, Ackerman DL, Rosen RM, et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry. 2004;65:565Y568.
10. Goodman WK, McDougle CJ, Barr LC, et al. Biological approaches to treatment-resistant obsessive compulsive disorder. J Clin Psychiatry. 1993;54(suppl):16Y26.
11. Marazziti D, Gemignani A, Dell’osso L. Trazodone augmentation in OCD: a case series report. CNS Spectr. 1999;4:48Y49.
12. Connor KM, Payne VM, Gadde KM, et al. The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients. J Clin Psychiatry. 2005;66:49Y51.
13. Van Ameringen M, Mancini C, Patterson B, et al. Topiramate augmentation in treatment-resistant obsessive-compulsive disorder: a retrospective, open-label case series. Depress Anxiety. 2006;23:1Y5.
14. Hollander E, Dell’Osso B. Topiramate plus paroxetine in treatment-resistant obsessive-compulsive disorder. Int Clin Psychopharmacol. 2006;21:189Y191.
15. Koran LM, Gamel NN, Choung HW, et al. Mirtazapine for obsessive-compulsive disorder: an open trial followed by double-blind discontinuation. J Clin Psychiatry. 2005;66:515Y520.
16. Pallanti S, Quercioli L, Bruscoli M. Response acceleration with mirtazapine augmentation of citalopram in obsessive-compulsive disorder patients without comorbid depression: a pilot study. J Clin Psychiatry. 2004;65:1394Y1399.
17. Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005;58:424Y428.
18. Lafleur DL, Pittenger C, Kelmendi B, et al. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl). 2006;184:254Y256.
19. Hezel DM, Beattie K, Stewart SE. Memantine as an augmenting agent for severe pediatric OCD. Am J Psychiatry. 2009;166:237.
20. Feusner JD, Kerwin L, Saxena S, et al. Differential efficacy of memantine for obsessive-compulsive disorder vs. generalized anxiety disorder: an open-label trial. Psychopharmacol Bull. 2009;42:81Y93.
21. Bolton J, Moore GJ, MacMillan S, et al. Case study: caudate glutamatergic changes with paroxetine persist after medication discontinuation in pediatric OCD. J Am Acad Child Adolesc Psychiatry. 2001;40:903Y906.
22. Carlsson ML. On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25:5Y26.
23. Chakrabarty K, Bhattacharyya S, Christopher R, et al. Glutamatergic dysfunction in OCD. Neuropsychopharmacology. 2005;30:1735Y1740.
24. Carlsson ML. On the role of cortical glutamate in obsessive-compulsive disorder and attention-deficit hyperactivity disorder, two phenomenologically antithetical conditions. Acta Psychiatr Scand. 2000;102:401Y413.
25. Yucel M, Wood SJ, Wellard RM, et al. Anterior cingulate glutamate-glutamine levels predict symptom severity in women with obsessive-compulsive disorder. Aust N Z J Psychiatry. 2008;42:467Y477.
26. Rosenberg DR, Mirza Y, Russell A, et al. Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls. J Am Acad Child Adolesc Psychiatry. 2004;43:1146Y1153.
27. Arnold PD, Rosenberg DR, Mundo E, et al. Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study. Psychopharmacology (Berl). 2004;174:530Y538.
28. Delorme R, Krebs MO, Chabane N, et al. Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder. Neuroreport. 2004; 15:699Y702.
29. Arnold PD, Sicard T, Burroughs E, et al. Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch Gen Psychiatry. 2006;63:769Y776.
30. Dickel DE, Veenstra-VanderWeele J, Cox NJ, et al. Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch Gen Psychiatry. 2006;63:778Y785.
31. Stewart SE, Fagerness JA, Platko J, et al. Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:1027Y1033.
32. Shugart YY, Wang Y, Samuels JF, et al. A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(6):886Y892.
33. Welch JM, Lu J, Rodriguiz RM, et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature. 2007;448:894Y900.
34. Pasquini M, Biondi M. Memantine augmentation for refractory obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1173Y1175.
35. Poyurovsky M, Weizman R, Weizman A, et al. Memantine for treatment-resistant OCD. Am J Psychiatry. 2005;162:2191Y2192.
36. Stewart SE, Stack DE, Farrell C, et al. Effectiveness of intensive residential treatment (IRT) for severe, refractory obsessive-compulsive disorder. J Psychiatr Res. 2005;39:603Y609.
37. Stewart SE, Yen CH, Stack DE, et al. Outcome predictors for severe obsessive-compulsive patients in intensive residential treatment. J Psychiatr Res. 2006;40:511Y519.
38. Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989;46:1006Y1011.
39. Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry. 1989;46:1012Y1016.
40. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561Y571.
41. Burt T, Ishak W. Outcome measurement in mood disorders. In: Ishak W, Burt T, Sederer L, eds. Outcome Measurement in Psychiatry. Washington, DC: American Psychiatric Publishing; 2002:35Y55.
42. Yovel I, Wilhelm S, Gershuny B. The ObsessiveYCompulsive Symptoms Rating Inventory: Development and Psychometric Analysis. 37th annual convention of the Association for the Advancement of Behavior Therapy, Boston, MA, 2003.
43. Mundt JC, Marks IM, Shear MK, et al. The Work and Social Adjustment Scale: a simple measure of impairment in functioning. Br J Psychiatry. 2002;180:461Y464.
44. Buchsbaum MS, Hollander E, Pallanti S, et al. Positron emission tomography imaging of risperidone augmentation in serotonin reuptake inhibitor-refractory patients. Neuropsychobiology. 2006;53: 157Y168.
45. Leckman JF, Rauch SL, Mataix-Cols D. Symptom dimensions in obsessive-compulsive disorder: implications for the DSM-V. CNS Spectr. 2007;12:376Y387, 400.
46. Stewart SE, Rosario MC, Baer L, et al. Four-factor structure of obsessive-compulsive disorder symptoms in children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2008;47:763Y772.
47. Geller DA, Biederman J, Stewart SE, et al. Impact of comorbidity on treatment response to paroxetine in pediatric obsessive-compulsive disorder: is the use of exclusion criteria empirically supported in randomized clinical trials? J Child Adolesc Psychopharmacol. 2003;13(suppl 1):S19YS29.
48. Nissen JB, Thomsen PH. [Significance of the glutaminergic system for obsessive-compulsive disorder]. Ugeskr Laeger. 2008;170: 2874Y2876.
49. Porter RH, Eastwood SL, Harrison PJ. Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia. Brain Res. 1997;751:217Y231.
50. Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr Clin North Am. 2000;23:563Y586.
51. Pralong E, Magistretti P, Stoop R. Cellular perspectives on the glutamate-monoamine interactions in limbic lobe structures and their relevance for some psychiatric disorders. Prog Neurobiol. 2002;67:173Y202.
52. Szeszko PR, Ardekani BA, Ashtari M, et al. White matter abnormalities in obsessive-compulsive disorder: a diffusion tensor imaging study. Arch Gen Psychiatry. 2005;62:782Y790.
53. Cannistraro PA, Makris N, Howard JD, et al. A diffusion tensor imaging study of white matter in obsessive-compulsive disorder. Depress Anxiety. 2007;24:440Y446.
54. Lieberman JA, Papadakis K, Csernansky J, et al. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology. 2009;34:1322Y1329.