Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: Effects of clomipramine and fluoxetine

Alvarez, Jean‐Claude; Gluck, Nathalie; Arnulf, Isabelle; Quintin, Philippe; Leboyer, Marion; Pecquery, R; Launay, Jean‐Marie; Pérez-Díaz, Fernando; Spreux‐Varoquaux, Odile

doi:10.1053/cp.1999.v66.103402001

Cited by 83 publications

(61 citation statements)

References 32 publications

(49 reference statements)

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“…Moreover, increased IP 3 concentration has been reported in patients with unipolar depression (Alvarez et al, 1999). The lack of diagnostic and familial specificity of these findings could be interpreted as an indication of shared genetic factors in OCD and affective disorders.…”

Section: Diagnostic and Familial Specificitymentioning

confidence: 96%

“…The decrease in whole blood 5-HT and 5-HTT binding are not unique to persons with OCD or at risk for developing such disorder, since these disturbances have also been observed in patients with affective disorders (Cleare, 1997;Alvarez et al, 1999) and in their unaffected relatives . Moreover, increased IP 3 concentration has been reported in patients with unipolar depression (Alvarez et al, 1999).…”

Section: Diagnostic and Familial Specificitymentioning

confidence: 97%

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Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Delorme

Betancur

Crinon

et al. 2005

Neuropsychopharmacol

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Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in nonaffected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Since peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients. We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT 2A receptorbinding characteristics, and platelet inositol trisphosphate (IP 3 ) content in a sample of OCD probands (n ¼ 48) and their unaffected parents (n ¼ 65), and compared them with sex-and age-matched controls (n ¼ 113). Lower whole blood 5-HT concentration, fewer platelet 5-HTT-binding sites, and higher platelet IP 3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (po0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT 2A receptor-binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands. The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.

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Section: Diagnostic and Familial Specificitymentioning

confidence: 96%

Section: Diagnostic and Familial Specificitymentioning

confidence: 97%

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Delorme

Betancur

Crinon

et al. 2005

Neuropsychopharmacol

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“…43 Changes in platelet 5-HT and SERT have been suggested as possible biomarkers for psychiatric illness (for review see Plein and Berk 44 ). Interestingly, Alvarez et al 45 reported a decrease in platelet SERT binding sites in depressed versus healthy individuals that was further reduced following 12-week administration of clomip ramine or fl uoxetine. Furthermore, a greater drop in platelet SERT binding sites was evident in antidepressant treatment responders versus nonresponders.…”

Section: Effects Of Chronic Antidepressant Exposure On Sertmentioning

confidence: 99%

Serotonin Transporters: Implications for Antidepressant Drug Development

White¹,

Walline²,

Barker³

2008

Drug Addiction

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A BSTRACTDue to the complexity of the disease, several hypotheses exist to explain the etiology of depression. The monoamine theory of depression suggests that disruptions in the sero tonergic and noradrenergic systems result in depressive symptoms. Therefore, the serotonin transporter (SERT) has become a pharmacological target for treating these symptoms. This review will discuss what is known about the molecular interactions of antidepressants with SERT. The effects of antidepressants on SERT regulation and expression in addition to the receptors that may be involved in mediating these effects will be addressed. Specifically, how changes to SERT expression following chronic antidepressant treatment may contribute to the therapeutic benefi ts of antidepressants will be discussed. Furthermore, the effects of SERT gene polymorphisms on antidepressant effi cacy will be examined. Finally, a brief overview of other hypotheses of depression will be addressed as well as factors that must be considered for future antidepressant development. K EYWORDS:SSRIs , antidepressant , serotonin transporter , depression , reuptake MONOAMINE THEORY OF DEPRESSIONFunctional defi ciencies in serotonin (5-hydroytryptamine, 5-HT) and norepinephrine (NE) have been implicated in the pathophysiology of depressive syndromes, and restoring the normal function of 5-HT-and NE-associated signaling pathway has been the target of antidepressants. Restoration of monoamine defi ciencies to normal levels as a therapeutic strategy is based on the monoamine hypothesis of depression. 1 The oldest antidepressants, the monoamine oxidase inhibitors (MAOIs), increase synaptic levels of 5-HT and NE by inhibiting the enzymatic degradation of these neurotransmitters. The tricyclic antidepressants (TCAs), as well as newer selective 5-HT reuptake inhibitors (SSRIs) and 5-HT/ NE reuptake inhibitors (SNRIs), all increase synaptic levels of 5-HT or NE by inhibiting reuptake via the 5-HT transporter (SERT) or NE transporter (NET), respectively. Emerging evidence indicates that the monoamine hypothesis of 5-HT and NE modulation fails to explain the whole mechanism of antidepressants. Other hypotheses, including the cytokine hypothesis of depression, the hypothalamic-pituitary-thyroid hypothesis of depression, as well as the role of brain-derived neurotrophic factor and cyclic AMP response element binding protein will be considered later in this review.

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“…Pandey et al (1999) found significantly lower PI-PLC activity and expression of the PLC isozyme PLC b1 in the brains of teenage suicide subjects relative to normal controls. In contrast, hyperactive PI signaling has been shown in platelets from depressed patients (Karege et al, 1996;Alvarez et al, 1999;Pandey et al, 2001). Elevated 5-HT-stimulated intracellular calcium has also been reported in platelets from unipolar depression (Delisi et al, 1998) and bipolar disorder (Suzuki et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Decreased Serotonin 5-HT2A Receptor-Stimulated Phosphoinositide Signaling in Fibroblasts from Melancholic Depressed Patients

Akın

Manier

Sanders‐Bush

et al. 2004

Neuropsychopharmacol

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Abnormalities in serotonin (5-HT) receptors and 5-HT receptor-mediated signal transduction systems have been widely reported in mood disorders. This study was intended to evaluate 5-HT 2A receptor-coupled activation of phosphatidylinositol (PI) hydrolysis in subtypes of depression. Samples for fibroblast culture were obtained from patients with major depression with or without melancholia, and normal controls. Dose response curves were determined for 5-HT-induced PI hydrolysis. PI response was determined for bradykinin and l-a-lysophosphatidic acid (LPA), alternative Gq-coupled receptor agonists. [ 125 I]LSD binding for 5-HT 2A also was conducted. Finally, Western blot analysis was performed for phospholipase C b1 (PLC b1 ) and Ga q/11 proteins. The maximum PI response observed with 5-HT was significantly lower in melancholics but not nonmelancholic patients relative to controls. Activation of PI hydrolysis by bradykinin and LPA was not reduced in melancholic vs melancholics and controls; responses to both agonists actually were increased in the melancholic group. [ 125 I]LSD binding, PLC b1 , and Ga q/11 protein levels did not differ between groups. The data raise the possibility that the reduced 5-HT 2A receptor-induced PI hydrolysis is intrinsic to the receptor itself or its coupling to Gq protein, and is not related to altered availability of the 5-HT 2A receptor, Gq or PLC.

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Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: Effects of clomipramine and fluoxetine

Cited by 83 publications

References 32 publications

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Serotonin Transporters: Implications for Antidepressant Drug Development

Decreased Serotonin 5-HT2A Receptor-Stimulated Phosphoinositide Signaling in Fibroblasts from Melancholic Depressed Patients

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