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Biochemistry and Neuropharmacology of obsessive compulsive disorder(OCD)

Biochemistry and Neuropharmacology of obsessive compulsive disorder(OCD)

Although they are an indirect assessment of brain function, data from biochemical challenge studies and pharmacological treatment outcome studies suggest that the orbital and cingulate cortex may be potential neuroanatomical sites of dysfunction in OCD. Data that address the neurochemistry of OCD have been collected under three conditions: steady-state assessment in untreated patients and comparisons to normal controls, pharmacological challenge studies in untreated patients, and changes in neurochemistry after pharmacological treatment. Each of these categories is discussed here. Biochemistry.Initially, cerebral spinal fluid (CSF) studies of adult patients with OCD primarily assessed serotonin levels and activity, but the f indings were inconsistent. Whereas some studies found higher levels of serotonin among OCD patients, others reported reduced levels. More recently, a broader range of substances has been investigated. For example, Swedo et al. examined eight different neurochemicals and their various combinations and found only a few significant differences between patients with OCD and normal control subjects including a significant negative correlation between 5-HIAA concentration and one of eight baseline OCD severity ratings (whereas three of eight correlations were significant after 5 weeks of treatment with clomipramine). Before treatment, the concentration of arginine vasopressin (a stressresponsive neurohormone) was negatively correlated with OCD symptoms, whereas corticotropin releasing hormone (another stress-responsive neurohormone) did not differentiate the two groups. The authors concluded that arginine vasopressin might be related to OCD symptom severity whereas 5-HIAA might be associated with treatment response. However, as discussed in greater detail in the functional neuroanatomy section, the only comparison group used consisted of normal controls. Thus, it is unclear if the negative correlation is specific to OCD or whether it is present in other disordered mood states. Using similar methodology, Altemus et al. (1992) reported that those with OCD had significantly higher levels of arginine vasopressin and corticotropin releasing hormone compared to normal controls, similar to the findings of Swedo et al..
However, in contrast to that study, Altemus et al. did not find a relationship between arginine vasopressin and any clinical rating of OCD. Corticotropin releasing factor level, on the other hand, was significantly related to scores on the Yale–Brown ObsessiveCompulsive scale but not with several other ratings of OCD. Thus, like the earlier studies that assessed serotonin, the relationship of these neurohormones to OCD is unclear. Another CSF neuropeptide, somatostatin, has also been the subject of investigation. As noted by these authors, when somatostatin is administered centrally to animals, it delays extinction of various behaviors or produces stereotyped behaviors that appear topographically similar to OCD rituals. When compared to those without a disorder, drug-free adult outpatients with OCD had higher levels of CSF somatostatin, a finding that is consistent with an earlier study of children with OCD. As Altemus et al. noted, the functional importance of the high somatostatin levels for patients with OCD is not known. What is known is that animal studies indicate an association of increased somatostatin with increased repetitive behaviors and that following pharmacotherapy with antidepressants, reductions occur in both OCD behaviors and somatostatin across multiple brain regions. However, the specificity of this decrease in somatostatin for reduction of OCD symptomatology is unclear (i.e., change also might occur in behaviors unrelated to OCD).
In contrast to assessment consisting solely of resting levels, a second series of studies used neuroendocrine challenge tests, most of which assessed serotonin (5-HT) function. These studies also produced inconsistent findings. Some reported increased 5-HT mediated responses after administering various pharmacological agents, whereas others reported normal or decreased responses, these conflicting results indicate that 5-HT mediated neuroendocrine responses are inconsistent and probably do not play an important role in the pathophysiology of OCD. Neuropharmacology.Numerous studies that date back to the late 1970s examined the response of various neurochemicals after treatment with selective serotonin reuptake inhibitors (SSRIs). A review of this extensive literature is beyond the scope of this chapter, and the interested reader is referred to Blier and de Montigny. Two studies are presented here for illustration. In an early study, treatment with clomipramine produced decreases in platelet serotonin concentration and an increase in standing plasma norepinephrine. More recently, patients treated with fluvoxamine had a normalized plasma prolactin response to d-fenfluramine (a pharmacological challenge agent), in contrast to the abnormal (decreased) response before treatment. Overall, this literature suggests that treatment with SSRIs may result in ‘‘normalization’’ of neurohormonal and neuroendocrine responses and that these changes are evident in areas of the brain that have been previously associated with dysfunction. For example, SSRIs enhance 5-HT release in the orbitofrontal cortex, but this enhanced release occurs only after a period of prolonged drug administration. These authors noted that because this neurochemical change in brain function occurs only after several weeks of pharmacotherapy, it is theoretically very important. It suggests that the mech anism of drug action is not simply by blocking serotonin re-uptake at the level of the individual synapse (which occurs almost immediately after drug ingestion). If this were the important mechanism of action, there should be an immediate decrease in OCD symptoms from taking the medication. Rather, the delayed onset of the clinical change is correlated with the time necessary to produce desensitization of the 5-HT terminals in the orbitofrontal cortex. Potentially, this is a very important finding in understanding brain pathology, but further studies are needed to verify this hypothesis.
In summarizing the literature on biochemistry and neuropharmacology, one of the most important limitations is that there are few studies that have used clinical control groups in addition to those without a psychiatric disorder. Thus, it is impossible to associate neurochemical changes specifically with OCD. For example, patients with anorexia nervosa show the same increased disregulation in arginine vasopressin as that of patients with OCD. Similarly, the positive correlation between arginine vasopressin and the dopamine metabolite HVA found in patients with OCD is also found in patients with schizophrenia. Similarities in neurochemistry across individuals with diverse types of disorders suggest that reported significant differences between patients with OCD and normal controls may reflect a general stress response rather than the pathophysiology of a specific disorder.

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