Nicholas H. Dodman

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

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 psychosocial functioning were collected by raters blinded to augmentation status. Matched controls were selected based on sex, initial OCD severity, psychosocial 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 nonresponse 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.

A canine chromosome 7 locus confers compulsive disorder susceptibility

of these receptors may lower dopamine content in the brain and increase the size of the striatum as seen in experimental animals and humans treated chronically with neuroleptics. As previously proposed, a hypodopaminergic state may also mediate the increase in the size of the striatum seen in chronic drug users. In conclusion, our findings highlight the negative consequences of PEMCS on the brain and behavior of adolescence and suggest that the a6 nAChR subunit may modify, at least in part, these effects.

The effect of diet on cribbing behavior and plasma β-endorphin in horses

Five cribbing horses and six control horses were used in a latin square design dietary study to investigate the effects of different diets on the frequency of cribbing behavior and plasma levels of beta-endorphin in the horse. Feeding grain or sweetened grain rations was found to cause a significant increase in the cribbing frequency whereas alfalfa pelleted hay was without significant effect on the frequency of the behavior. Baseline beta-endorphin levels in cribbing horses were half those of the non-cribbing controls and remained signif- icantly lower during the feeding trials. These results are discussed as they apply to treat- ment of cribbing horses and in terms of the underlying mechanism of cribbing.

Behavioral disorders in veterinary practice: Relevance to psychiatry

Debates about the advantages and limitations of animal models for psychiatric research do not usually involve behavioral disorders seen in veterinary practice. Nevertheless, naturally occurring behavioral symptoms in domestic animals may comprise important models or provide a valuable perspective for human psychiatric disorders. We review the promising but preliminary research in this area.

Thunderstorm phobia in dogs: an Internet survey of 69 cases

To learn more about predispositions for, signs, and progression of canine thunderstorm phobia, a survey for owners was posted on the Internet. Questions addressed signalment, age of onset, behavior during storms, and treatments tried. Sixty-nine responses were received. Herding dogs and herding crossbreeds accounted for the majority of dogs. Seventeen of 41 dogs with a known age of onset began exhibiting thunderstorm phobia <1 year of age. Various characteristic responses of dogs to storms were described. Improved knowledge of the demographics of thunderstorm phobia, its development, and presentation will assist in understanding the genesis and progression of the condition.

The effect of the NMDA receptor blocker, dextromethorphan, on cribbing in horses

Stereotypic cribbing in horses is thought to involve excess dopaminergic activity within the striatum. Various models of stress-induced stereotypies including cribbing in horses postulate that stress stimulates the release of endorphins, triggering the release of striatal dopamine. Dopamine in turn activates basal ganglia motor programs, reinforcing behavior via a reward mechanism. Furthermore, the release of dopamine by endorphins has been shown to depend on activation of NMDA receptors. In the present study, horses identified as cribbers and volunteered by their owners were treated with the NMDA receptor antagonist dextromethorphan (DM). When DM was administered via jugular injection (1 mg/kg), eight of nine horses responded with reductions in cribbing rate (CR) compared to baseline, and cribbing was suppressed completely for a period of time in almost half of the horses tested.

Observations on the use of the Wernberg dip-lift carbon dioxide apparatus for pre-slaughter anaesthesia of pigs.

SUMMARY Groups of pigs were anaesthetized on a number of occasions with concentrations of CO 2 ranging from 50%–80%. In all cases the exposure time was 45 seconds. Behavioural effects before loss of consciousness and recovery time after exposure to the varying concentrations of CO 2 were noted. In some pigs electrocardiograph recordings were made during recovery and in others arterial or venous blood samples were taken for blood gas analysis. The results indicate that at the concentrations of CO 2 which are used commercially for stunning, that is 66%–70%, approximately half of the pigs were standing within one minute of their return to atmospheric air. Some degree of excitement was seen at all CO 2 concentrations but it was difficult to assess whether this was more marked at higher concentrations. Certain individual pigs, however, reacted violently whatever the concentration. With concentrations of CO 2 ranging from 76%–80% all the pigs in this trial remained in lateral recumbency for at least a minute after their removal from the CO 2 chamber and in some cases they remained recumbent for over two minutes. In all cases where the electrocardiogram was recorded the pigs had paroxysmal ventricular tachycardia immediately before standing. The blood gas results show that all the pigs had some degree of hypoxaemia and that they all had metabolic and respiratory acidosis.

Rare missense neuronal cadherin gene ( CDH2 ) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher’s exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.

Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by defects in communication and social interactions, as well as stereotypic behaviors. Symptoms typically worsen with anxiety and stress. ASD occur in early childhood, often present with regression and have a prevalence of 1 out of 68 children. The lack of distinct pathogenesis or any objective biomarkers or reliable animal models hampers our understanding and treatment of ASD. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have proinflammatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell (MC)-dependent skin vascular permeability in rodents. CRH also induced NT receptor gene and protein expression in MCs, which have been implicated in ASD. Here we report that serum of ASD children (4–10 years old) has significantly higher NT and CRH levels as compared with normotypic controls. Moreover, there is a statistically significant correlation between the number of children with gastrointestinal symptoms and high serum NT levels. In Bull Terriers that exhibit a behavioral phenotype similar to the clinical presentation of ASD, NT and CRH levels are also significantly elevated, as compared with unaffected dogs of the same breed. Further investigation of serum NT and CRH, as well as characterization of this putative canine breed could provide useful insights into the pathogenesis, diagnosis and treatment of ASD.

Brain structural abnormalities in Doberman pinschers with canine compulsive disorder.

Obsessive compulsive disorder (OCD) is a debilitating condition, the etiology of which is poorly understood, in part because it often remains undiagnosed/untreated for a decade or more. Characterizing the etiology of compulsive disorders in animal models may facilitate earlier diagnosis and intervention. Doberman pinschers have a high prevalence of an analogous behavioral disorder termed canine compulsive disorder (CCD), which in many cases responds to treatments used for OCD. Thus, studies of CCD may help elucidate the etiology of compulsive disorders. We compared brain structure in Dobermans with CCD (N=8) and unaffected controls (N=8) to determine whether CCD is associated with structural abnormalities comparable to those reported in humans with OCD. We obtained 3 Tesla magnetic resonance structural and diffusion images from anesthetized Dobermans and subjected images to segmentation, voxel based morphometry, and diffusion tensor analyses. CCD dogs exhibited higher total brain and gray matter volumes and lower dorsal anterior cingulate cortex and right anterior insula gray matter densities. CCD dogs also had higher fractional anisotropy in the splenium of the corpus callosum, the degree of which correlated with the severity of the behavioral phenotype. Together, these findings suggest that CCD is associated with structural abnormalities paralleling those identified in humans with OCD. Accordingly, the CCD model, which has a number of advantages over other animal models of OCD, may assist in establishing the neuroanatomical basis for and etiology of compulsive disorders, which could lead to earlier diagnosis of and new treatments for humans and animals with these disorders.