Stereoselective Metabolism of Citalopram in Plasma and Cerebrospinal Fluid of Depressive Patients

Nikisch, Georg; Mathé, Aleksander A.; Czernik, Adelheid; Eap, Chin B.; Jiménez-Vasquez, Patricia; Brawand-Amey, Marlyse; Baumann, Pierre

doi:10.1097/01.jcp.0000125680.89843.a6

Cited by 35 publications

(42 citation statements)

References 44 publications

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“…The knowledge that neuronal uptake blockade following antidepressant administration occurs rapidly but therapeutic effects may take from 2 to 6 weeks to occur 70 has been difficult to reconcile both in terms of the etiology of the disease and the therapeutic mechanism of SSRIs. In agreement with our results documenting a reduction in internal jugular venous overflow of 5-HIAA following SSRI administration, improvement in symptoms coupled with a reduction in CSF 5-HIAA levels in patients with MDD following therapy with citalopram, 71,72 venlafaxine hydrochloride, 73 fluvoxamine, and fluoxetine 43,74 have previously been described. Citalopram administration in chronically stressed rats normalizes the elevated expression of tryptophan hydroxylase.…”

Section: Commentsupporting

confidence: 80%

Elevated Brain Serotonin Turnover in Patients With Depression

Barton¹,

Esler²,

Dawood³

et al. 2008

Arch Gen Psychiatry

190

107

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Context:The biological basis for the development of major depressive disorder (MDD) remains incompletely understood.Objective: To quantify brain serotonin (5-hydroxytryptamine ) turnover in patients with MDD.Design: Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated.Setting: Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. Conclusions: Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD. Psychiatry. 2008;65(1):38-46 T HE ETIOLOGY OF MAJOR DEpressive disorder (MDD) has been linked to brain monoaminergic neuronal dysfunction. Arch Gen1,2 Of particular interest is the role of brain serotonin (5-hydroxytryptamine [5-HT]) in MDD. The diversity of roles played by serotonin coupled with the lack of a demonstrated relationship between different clinical presentations and biochemical abnormalities has hampered the development of sensitive markers of the disease. Indeed, brain serotonin-releasing neurons subserve diverse although incompletely understood functions related to emotions and behavior, feeding and adiposity, 3 and light stimulation. 4 We have previously demonstrated influences of obesity and feeding 5 and season and sunlight 6 on brain serotonin turnover in humans. The principal means of intraneuronal metabolism of serotonin is via oxidative deamination by monoamine oxidase resulting in formation of 5-hydroxyindoleacetic acid (5-HIAA) (Figure 1). Deamination followed by reduction, conjugation with sulfate or glucuronide, and

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Section: Commentsupporting

confidence: 80%

Elevated Brain Serotonin Turnover in Patients With Depression

Barton¹,

Esler²,

Dawood³

et al. 2008

Arch Gen Psychiatry

190

107

View full text Add to dashboard Cite

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“…Based on the substrate depletion experiments, CL int due to SCIT PROP formation was approximately 70% of the CL int accounted for by SDCIT formation. However, in line with previous studies (Bondolfi et al, 1996(Bondolfi et al, , 2000Nikisch et al, 2004), plasma concentrations of SCIT PROP exceeded those of SDCIT in most of the patients. This finding indicates that subsequent elimination of SCIT PROP, probably via glucuronidation (Oyehaug et al, 1984;Dalgaard and Larsen, 1999), is slower than for SDCIT.…”

Section: Novel Cyp2c19-mediated Metabolic Pathway Of S-citalopramsupporting

confidence: 76%

“…Although the distributional characteristics of this metabolite are essentially unknown, a study by Nikisch et al (2004) reported that SCIT PROP was present in the cerebrospinal fluid of patients treated with racemic CIT. However, the pharmacodynamic properties of SCIT PROP were not investigated, and a potential contribution from SCIT PROP to the clinical effects or side effects of SCIT treatment is therefore unknown.…”

Section: Novel Cyp2c19-mediated Metabolic Pathway Of S-citaloprammentioning

confidence: 99%

“…Previous studies indicate that the initial step of aldehyde formation might be mediated by monoamine oxidase (Rochat et al, 1998;Kosel et al, 2001Kosel et al, , 2002Nikisch et al, 2004;Testa and Krämer, 2007). Furthermore, in vivo biotransformation of aldehydes to carboxylic acids may be catalyzed by aldehyde dehydrogenase (Sladek et al, 1989;Testa and Kramer, 2007).…”

Section: Novel Cyp2c19-mediated Metabolic Pathway Of S-citaloprammentioning

confidence: 99%

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Identification of a Novel CYP2C19-Mediated Metabolic Pathway ofS-Citalopram in Vitro

Rudberg

Reubsaet²,

Hermann³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Systemic exposure of the antidepressant S-citalopram (escitalopram, SCIT) differs several-fold according to variable cytochrome P450 2C19 activity, demonstrating the importance of this enzyme for the metabolic clearance of SCIT in vivo. However, previous studies have indicated that the involvement of CYP2C19 in formation of the metabolite N-desmethyl S-citalopram (SDCIT) is limited. Therefore, the purpose of the present in vitro study was to investigate to what extent the CYP2C19-mediated clearance of SCIT was due to a metabolic pathway different from N-desmethylation and to identify the product(s) of this possible alternative metabolic reaction. CYP2C19-mediated metabolism of SCIT was investigated using recombinant Supersomes expressing human CYP2C19. Initial experiments showed that approximately half of the CYP2C19-mediated clearance of SCIT was accounted for by the N-desmethylation pathway. Subsequent experiments identified that, in addition to SDCIT, the propionic acid metabolite of SCIT (SCIT PROP) was formed by CYP2C19 in vitro. Formation of SCIT PROP accounted for 35% of total CYP2C19-mediated clearance of SCIT (calculated as the ratio between metabolite formation rate and substrate concentration at low substrate concentration). Moreover, analysis of samples from six CYP2C19-genotyped patients treated with SCIT indicated that differences in serum concentrations of SCIT between CYP2C19 genotypes may be due to a combined effect on SCIT PROP and SDCIT formation. Identification of SCIT PROP as a metabolic pathway catalyzed by CYP2C19 might explain why impaired CYP2C19 activity has a substantially larger effect on SCIT exposure than estimated from in vitro data based solely on formation of SDCIT.

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“…These values are within clinically relevant therapeutic ranges (Perry et al, 1994;Nikisch et al, 2004). There were no significant differences between treatment groups in trials to criterion for the SD task on the training day (F 1,39 ¼ 0.526, p ¼ 0.47 for Stress; F 2,39 ¼ 0.902, p ¼ 0.41 for drug).…”

Section: Experiments 2: Effect Of Chronic Antidepressant Drug Treatmenmentioning

confidence: 56%

Chronic Unpredictable Stress Induces a Cognitive Deficit and Anxiety-Like Behavior in Rats that is Prevented by Chronic Antidepressant Drug Treatment

Bondi

Rodríguez

Gould

et al. 2007

Neuropsychopharmacol

346

263

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Chronic stress is a risk factor for the development of many psychopathological conditions in humans, including major depression and anxiety disorders. There is a high degree of comorbidity of depression and anxiety. Moreover, cognitive impairments associated with frontal lobe dysfunction, including deficits in cognitive set-shifting and behavioral flexibility, are increasingly recognized as major components of depression, anxiety disorders, and other stress-related psychiatric illnesses. To begin to understand the neurobiological mechanisms underlying the cognitive and emotional consequences of chronic stress, it is necessary to employ an animal model that exhibits similar effects. In the present study, a rat model of chronic unpredictable stress (CUS) consistently induced a cognitive impairment in extradimensional set shifting capability in an attentional set shifting test, suggesting an alteration in function of the medial prefrontal cortex. CUS also increased anxiety-like behavior on the elevated plus-maze. Further, chronic treatment both with the selective norepinephrine reuptake blocker, desipramine (7.5 mg/kg/day), and the selective serotonin reuptake blocker, escitalopram (10 mg/kg/ day), beginning 1 week before CUS treatment and continuing through the behavioral testing period, prevented the CUS-induced deficit in extradimensional set-shifting. Chronic desipramine treatment also prevented the CUS-induced increase in anxiety-like behavioral reactivity on the plus-maze, but escitalopram was less effective on this measure. Thus, CUS induced both cognitive and emotional disturbances that are similar to components of major depression and anxiety disorders. These effects were prevented by chronic treatment with antidepressant drugs, consistent also with clinical evidence that relapse of depressive episodes can be prevented by antidepressant drug treatment.

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Stereoselective Metabolism of Citalopram in Plasma and Cerebrospinal Fluid of Depressive Patients

Cited by 35 publications

References 44 publications

Elevated Brain Serotonin Turnover in Patients With Depression

Elevated Brain Serotonin Turnover in Patients With Depression

Identification of a Novel CYP2C19-Mediated Metabolic Pathway ofS-Citalopram in Vitro

Chronic Unpredictable Stress Induces a Cognitive Deficit and Anxiety-Like Behavior in Rats that is Prevented by Chronic Antidepressant Drug Treatment

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