Specificity of Serotonin Reuptake Inhibitors in the Treatment of Obsessive-Compulsive Disorder

Goodman, Wayne K.

doi:10.1001/archpsyc.1990.01810180077011

Cited by 299 publications

(112 citation statements)

References 89 publications

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“…In general, OCD symptoms can best be managed with the serotonin reuptake inhibitor clomipramine, the selective serotonin reuptake inhibitors (SSRIs) or behavioral therapy (Leonard et al, 1988;Goodman, 1999;Vythilingum et al, 2000). The selective response of OCD patients to clomipramine or SSRIs has led to the hypothesis that changes in the central serotonergic systems may be the mechanism by which these compounds exert their effect (Leonard et al, 1988;Goodman et al, 1990Goodman et al, , 1992Baumgarten and Grozdanovic, 1998). Direct evidence that serotonergic perturbations are implicated in the neurobiology of OCD; however, is sparse (Stein, 2002).…”

Section: Introductionmentioning

confidence: 99%

Changes in Thalamus–Hypothalamus Serotonin Transporter Availability during Clomipramine Administration in Patients with Obsessive–Compulsive Disorder

Zitterl

Aigner

Stompe

et al. 2008

Neuropsychopharmacol

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To the authors' knowledge there is as of yet no study demonstrating in vivo alterations in human serotonin transporters (SERT) during clomipramine treatment in patients with obsessive-compulsive disorder. The only study in which SERT binding has been investigated in obsessive-compulsive disorder (OCD) patients before and after treatment is a small pilot study by Stengler-Wenzke et al (2006), who treated five OCD patients with citalopram. In the study at hand, we measured transporter availability in the thalamus-hypothalamus with [ 123 I] b-CIT single photon emission computed tomography (SPECT) in 24 patients with DSM-IV OCD. All patients displayed prominent behavioral checking compulsions (OC-checkers). At baseline and upon medication after 12 weeks of treatment with clomipramine (150 mg daily) 24 non-depressed OC-checkers underwent a SPECT measurement of brain SERT availability using [ 123 I]-2b-carbomethoxy-3b-(4-iodophenyl)tropane. For quantification of brain serotonin transporter availability, a ratio of specific to nondisplaceable [ 123 I] b-CIT brain binding was used (BP ND ¼ (thalamus and hypothalamusÀcerebellum)/cerebellum). The SERT availability was compared between baseline and after treatment and correlated with severity of OC symptomatology and treatment response as assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). After treatment with clomipramine patients showed a 48% reduced brain serotonin transporter availability in the thalamus-hypothalamus, as compared with values at baseline (0.72±0.12 vs 1.39±0.18, po0.001). Correlations between brain SERT availability and OC symptomatology (Y-BOCS scores) revealed significantly negative associations both at baseline and after treatment (r ¼ À0.46; po0.05 and r ¼ À0.53; po0.01 respectively). These data suggest that the SERT availability values could be considered a biological indicator of disease severity. Moreover, in search of predictors we found that higher pretreatment SERT availability significantly predicted better treatment response 12 weeks later (B ¼ 14.145 ± 4.514; t ¼ 3.133; p ¼ 0.005). These results provide further support for an important role of alterations in serotonergic neurons in the pathophysiology of OCD.

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Section: Introductionmentioning

confidence: 99%

Changes in Thalamus–Hypothalamus Serotonin Transporter Availability during Clomipramine Administration in Patients with Obsessive–Compulsive Disorder

Zitterl

Aigner

Stompe

et al. 2008

Neuropsychopharmacol

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“…This is currently believed to involve a disturbance in frontocortical-subcortical neuroanatomical pathways, including the orbitofrontal cortex, the basal ganglia, and the thalamushypothalamus, and neurochemical abnormalities of central serotonergic functioning. The hypothesis of a serotonergic dysfunction in OCD has arisen mainly as an indirect conclusion based on neuropharmacologic studies supporting a high selectivity of drug response in OCD to serotonin reuptake inhibiting agents (Leonard et al, 1988;Goodman et al, 1990). Radioligands used in neuroimaging techniques allow for the study of central neurotransmitter systems.…”

Section: Introductionmentioning

confidence: 99%

[123I]-β-CIT SPECT Imaging Shows Reduced Thalamus–Hypothalamus Serotonin Transporter Availability in 24 Drug-Free Obsessive-Compulsive Checkers

Zitterl

Aigner

Stompe

et al. 2006

Neuropsychopharmacol

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Numerous findings indicate alterations in brain serotonin systems in obsessive-compulsive disorder (OCD). We investigated the in vivo availability of thalamus-hypothalamus serotonin transporters (SERT) in patients with DSM-IV OCD who displayed prominent behavioral checking compulsions (OC-checkers). Four hours after injection of [ 123 I]-2b-carbomethoxy-3b-(4-iodophenyl)tropane ([ 123 I]-b-CIT), single photon emission computed tomography (SPECT) scans were performed in 24 medication-free non-depressed OC-checkers and 24 age-and gender-matched healthy controls. For quantification of brain serotonin transporter availability, a ratio of specific to non-displaceable [ 123 I]-b-CIT brain binding was used (V 00 3 ¼ (thalamus and hypothalamusÀcerebellum)/cerebellum). Drug-free nondepressed OC-checkers showed an 18% reduced brain serotonin transporter availability in the thalamus and hypothalamus, as compared with healthy control subjects (1.3870.19 vs 1.6970.21; po0.001). There was a strong negative correlation between severity of OC symptomatology (Y-BOCS scores) and SERT availability (r ¼ À0.80; po0.001). Moreover, we found a significant positive correlation between illness duration and serotonin transporter availability (r ¼ 0.43; po0.05). This first report of significantly reduced [ 123 I]-b-CIT binding in the thalamus-hypothalamus region in OC-checkers suggests reduced brain serotonin transporter availability, which is more pronounced with increased severity of OC symptomatology and short duration of illness. The results provide direct evidence for an involvement of the serotonergic system in the pathophysiology of OCD.

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“…8 In particular, the clear efficacy of potent serotonin reuptake inhibitors (SRIs), including clomipramine, 9 fluvoxamine, 10 fluoxetine, 11 sertraline, 12 and paroxetine, 13 and their greater efficacy when directly compared to drugs that potently inhibit norepinephrine uptake, 14 supports the hypothesized importance of serotonin (5-hydroxytryptamine, 5-HT) in the treatment of OCD. This class of drugs acts on the serotonin transporter protein (5-HTT); the acute blockade of 5-HT uptake into nerve terminals at the 5-HTT by these drugs is likely to be a critical initial event in a series of neurochemical effects that result in improvement of obsessive-compulsive symptoms.…”

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confidence: 99%

“…14 It was previously postulated that any comprehensive theory about the pathophysiology of OCD must take into consideration this differential treatment response finding. 14 A significant association of depression and anxietyrelated traits with a polymorphism in the human serotonin transporter protein gene (SLC6A4) promoter was recently reported among 505 subjects consisting predominately of European-American male siblings, other family members and volunteers. 2 Subjects with either one or two copies of the 's' (short) allele had higher scores on the NEO personality inventory factor of Neuroticism 15 than did individuals homozygous for the 'l' (long) allele of the SLC6A4 promoter polymorphism.…”

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confidence: 99%

Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder

et al. 1998

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Obsessive compulsive disorder (OCD) is characterized by recurrent and intrusive thoughts that are distressing (obsessions) and/or repetitive behaviors or mental acts that the person feels driven to perform (compulsions). OCD has a partly genetic basis. For treatment of OCD, potent serotonin reuptake inhibitor (SRI) drugs (clomipramine (Anafranil), fluvoxamine (Luvox), fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil)), which act on the serotonin transporter protein, are uniquely efficacious. A polymorphism in the promoter region of the gene (SLC6A4) encoding this protein, 1 was recently reported to affect protein expression and to be associated with measures of anxiety and depression 2 and with autism (using a family-controlled transmission disequilibrium test (TDT) design). 3 SLC6A4 therefore has strong a priori support for potentially influencing risk for OCD: the protein it encodes is a medication target; a polymorphism in the gene affects function; and that polymorphism has been shown to be associated with behavioral phenotypes. We used the TDT with a set of 34 European-American family trios, 30 unrelated and four drawn from an extended pedigree, to test for linkage disequilibrium between OCD and alleles at the SLC6A4 promoter polymorphic locus. Of 35 heterozygous parents, 24 transmitted the 'l' SLC6A4 allele and 11 transmitted the 's' allele ( 2 TDT = 4.83; PϽ0.03). Considering only the 13 SRI drug nonresponders, there were 13 heterozygous parents, of whom 10 transmitted the 'l' allele and three the 's' allele ( 2 TDT = 3.77; PϽ0.052). These data provide preliminary support for association and linkage disequilibrium between the SLC6A4 'l' allele and OCD.

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Specificity of Serotonin Reuptake Inhibitors in the Treatment of Obsessive-Compulsive Disorder

Cited by 299 publications

References 89 publications

Changes in Thalamus–Hypothalamus Serotonin Transporter Availability during Clomipramine Administration in Patients with Obsessive–Compulsive Disorder

Changes in Thalamus–Hypothalamus Serotonin Transporter Availability during Clomipramine Administration in Patients with Obsessive–Compulsive Disorder

[123I]-β-CIT SPECT Imaging Shows Reduced Thalamus–Hypothalamus Serotonin Transporter Availability in 24 Drug-Free Obsessive-Compulsive Checkers

Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder

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