Aetiology Neurotransmitters

Many clinical trials of various serotonergic drugs lend support to the hypothesis that a dysregulation of serotonin is involved in OCD. However, this does not necessarily reflect on pathogenesis. Abnormality of the serotonergic system, and particularly the hypersensitivity of postsynaptic 5-HT receptors, constitutes the leading hypothesis for the underlying pathophysiology of OCD. ^J.. ,19,20,21,2. ,2 ,24,25,26,2 ,2 ,2.9,3.0and3!)

Clinical studies have assayed cerebrospinal levels of serotonin metabolites (e.g. 5-hydroxyindoleacetic acid ( 5-HIAA) a 5-HT metabolite that serves as an index of 5-HT turnover)'1 19) and affinities of imipramine binding sites on platelets (labelling with [ 3H]imipramine shows that it binds to serotonin reuptake sites),(20,21,2 and 23) although results have been inconsistent in patients with OCD. A study supporting the relationship between a decreased function of the serotonergic system and a positive response to selective serotonin reuptake inhibitors ( SSRIs), demonstrated normalization of the number of platelet 5-HT transporters following treatment with different SSRIs/24 In an earlier study, patients who responded to clomipramine had higher pretreatment levels of 5-HIAA than the non-responders. (18) Moreover, the clinical improvement was positively correlated with a decrease in the concentration of 5-HIAA in cerebrospinal fluid. (1.8)

Another approach is to examine peripheral measures of serotonergic and noradrenergic function in patients with OCD. In one study, clinical improvement during clomipramine therapy closely correlated with pretreatment platelet serotonin concentration and monoamine oxidase activity, as well as with the decrease in both measures during clomipramine administration.(25) Moreover, only the plasma levels of clomipramine (a potent 5-HT reuptake inhibitor), but not the plasma levels of its primary metabolite, desmethyl clomipramine (which has noradrenergic properties), correlated significantly with an improvement in OCD symptoms. These findings suggest that the effects of anti-obsessive medications, clomipramine in this study, on serotonin function are pertinent to the anti-obsessional action observed.

Additional support for the importance of serotonin in the therapeutic response to serotonin reuptake inhibitors ( SRIs) in OCD came from a study by Benkelfat et al.,(3!> in which the investigators administered the serotonin receptor antagonist metergoline and placebo to 10 patients with OCD in a double-blind crossover study. Patients receiving clomipramine on a long-term basis responded with greater anxiety to a 4-day administration of metergoline when compared with the placebo phase of the study.

Additional evidence for disturbances of the serotonergic system in OCD was provided by challenge studies. Challenges with L-tryptophan, (26> m-chlorophenylpiperazine (mCPP),(Z,.2Z> sumatriptan (a 5-HT1D agonist(6)), ipsapirone (a 5-HT1A receptor ligand(28)), and MK-212 (a 5-HT1A and 5-HT2C agonist^9'), among others, were used to evaluate whether they worsen obsessive-compulsive symptoms or whether they elicit different physiological responses (thermal or neuroendocrine) in patients with OCD compared with controls. Only two compounds (m-chlorophenylpiperazine and sumatriptan) have shown behavioural hypersensitivity and neuroendocrine hyposensitivity to be characteristic of the OCD challenge response. These studies may have the potential to pinpoint the receptor subtype involved in OCD, raising the possibility that 5-HT 1D and 5-HT2C receptors, but not 5-HT1A, could be involved in OCD. (3°)

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