Serotonin. The serotonergic hypothesis of OCD is based on, among other pieces of evidence, the selective efficacy of drugs with specific serotonergic activity (Ananth et al., 1981; Insel et al., 1985) and challenge tests with serotonergic agonists. Challenges with sumatriptin (Bastani et al., 1990) and mCPP metacholorophenyl-piperazine (Zohar et al., 1987, 1988; Pigott et al., 1991) show that OCD symptoms are exacerbated by these serotonin agonists. In contrast, metergoline, a serotonin antagonist, has been shown to protect against mCPP's behavioral effects (Pigott et al., 1991). Medications that block serotonin reuptake, such as clomipramine and the selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, sertraline, paroxetine, and citalo-pram, have been shown to be the most effective pharmacologic treatments for OCD. Clomipramine is a tricyclic antidepressant that is a relatively selective and potent inhibitor of active serotonin uptake in the brain (it also blocks histamine H2 receptors, cholinergic, and adrenergic receptors and has antidopaminergic properties). Its metabolite, desmethylclomipramine, is also effective in blocking serotonin reuptake (and reuptake of noradrenaline) (Vythilingum et al., 2000). The response of OCD symptoms to clomipramine but not to the equally effective antidepressant desipramine (Ananth et al., 1981; Insel et al., 1985; Leonard et al., 1989) indicates a remarkable specificity of effect for the serotonin uptake inhibitors for OCD. No unselected group of depressed patients, for example, would show such a differential response.
Additional evidence for the serotonergic hypothesis is provided by several studies in children and adolescents with OCD. The first demonstrated that response to clomipramine correlated with pretreatment platelet serotonin concentration (Flament et al., 1985, 1987). A high pretreatment level of serotonin was a strong predictor of clinical response, and within this sample platelet serotonin concentrations were lower in the more severely ill patients. However, there were no differences in serotonin concentration from age-/sex-matched controls. A study of cerebrospinal fluid monoamines in 43 children and adolescents with OCD revealed that 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of serotonin, correlated most strongly with response to clomipramine therapy; that is, the most successful responders had the highest levels of 5-HIAA in the cerebrospinal fluid (Swedo et al., 1992). A more recent study, employing positron emission tomography (PET) and serotonergic ligands, found evidence for decreased serotonin synthesis in the ventral prefrontal cortex and caudate nucleus in treatment naive OCD patients 8 to 13 years of age (Rosenberg et al., 1998). The latter study provides support for both the serotonergic hypothesis of OCD and also for dysfunction within the basal ganglia-frontal cortex circuitry.
The serotonergic hypothesis is undoubtedly too simplistic to account for the complexity of OCD. If the defect were limited to serotonergic dysfunction, clomipramine and the SSRIs should be effective in eliminating symptoms in all patients; unfortunately, this is not the case. Partial treatment response to SSRIs is common in OCD, but up to 40 percent of patients will fail to have any significant improvement with SSRI administration (Hollander et al., 2000). Individual patients also have variable patterns of response to the different SSRIs, suggesting that the nonserotonergic properties of the medications may also play key roles and that the antiobsessional effect may actually result from an alteration in the balance of serotonin and other monoamines and/or changes in receptor functions (Murphy et al., 1989). Support for this hypothesis is provided by the results of meta-analyses demonstrating that clomipramine (a neuro-chemically relatively nonspecific or "dirty" drug) is significantly more effective than the SSRIs, fluoxetine, fluvoxamine, and sertraline, in the treatment of OCD (Greist et al., 1995).
Dopamine and Other Neurotransmitters. Dopaminergic dysfunction in OCD is suggested not only by the obsessive-compulsive symptoms in patients with basal ganglia disorders but also by the increase in obsessive-compulsive symptoms following high-dose stimulant administration (Frye and Arnold, 1981) and occasional amelioration of symptoms following dopamine blocking agents (Goodman et al., 1990; McDougle 1997). High-dose stimulant administration has been thought to produce simple stereotypies, rather than more complex compulsive or obsessive behavior; however, "compulsive" symptoms have been observed in children with attention deficit disorder and hyperactivity during treatment with high-dose amphetamines (1 mg/kg d-amphetamine or 2 mg/kg methylphenidate) (Borcherding et al., 1990). For example, a 7-year-old boy spent several hours each evening vacuuming the carpet in his home, and another played with Lego blocks for 2 days, stopping only to eat and sleep. As in OCD, the children also became overly concerned with details and erased holes in their papers trying to get a single letter perfectly shaped. However, no psychological distress accompanied the obsessive-compulsive behaviors in the stimulant-induced cases, leading to speculation that repetitive thoughts and behaviors (obsessions and compulsions) may result from dopaminergic overactivity but that serotonin dysregula-tion is required for ego-dystonicity error. Observations in Tourette disorder appear to provide support for this hypothesis. In Tourette, motor and vocal tics are not reported to be ego-dystonic (although they may become physically uncomfortable) and appear to result from dopaminergic overactivity overcoming serotonergic inhibition. In contrast, if OCD is primarily a serotonergic defect, the disorder might arise from an inability to inhibit normal dopaminergic activity and the inappropriate release of dopaminergic-derived fixed action patterns (obsessions and compulsions). Ego-dystonicity could then be related to the primary serotonin defect, or secondary to the loss of volitional control (Swedo and Rapoport, 1990).
Was this article helpful?
Are You Depressed? Heard the horror stories about anti-depressants and how they can just make things worse? Are you sick of being over medicated, glazed over and too fat from taking too many happy pills? Do you hate the dry mouth, the mania and mood swings and sleep disturbances that can come with taking a prescribed mood elevator?