Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G, Owens MJ, Nemeroff CB, Rajeevan N, Baldwin RM, Seibyl JP, Innis RB, Charney DS.
Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography.
Biol Psychiatry. 1998 Dec 1;44(11):1090-8.
"BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression." [Abstract]

Hrdina PD.
Antidepressant binding: implications for the mode of action and the biology of depression.
Prog Neuropsychopharmacol Biol Psychiatry. 1983;7(4-6):457-62.
"(3H)Imipramine binding sites in the brain are localized mainly on serotonergic nerve terminals. In the hippocampus of rats with a lesion of serotonergic nerve terminals produced by neonatal administration of 5,7-DHT, the depletion of serotonin was paralleled by a decrease in (3H)imipramine recognition sites. (3H)Imipramine recognition sites in brain tissue or platelets are associated with serotonin uptake sites. A significant correlation exists between the potency of a series of antidepressants and other compounds to displace high affinity (3H)imipramine binding and to inhibit the neuronal uptake of serotonin but not of norepinephrine. There is a significant correlation between the ability of drugs to displace (3H)desipramine binding and to inhibit norepinephrine but not serotonin reuptake. (3H)Desipramine recognition sites are located, at least in part, at noradrenergic nerve terminals since destruction of these terminals by 6-OH-DA results in parallel decrease in (3H)desipramine, but not in (3H)imipramine binding. The high affinity recognition sites of (3H)imipramine and (3H)desipramine in the brain could be physiologically and pharmacologically relevant regulatory sites associated with neuronal uptake of serotonin and norepinephrine, respectively. Treatments which clinically lead to improvement of depression (eg. antidepressants, ECT, REM sleep deprivation) were shown to "down-regulate" (3H)imipramine binding sites in brain of experimental animals. The density of (3H)imipramine binding sites was shown to be lower in platelets from depressive patients and in brains of suicide victims. It appears that decreased binding of (3H)imipramine to platelets of depressed patients is a promising biological marker of depression, although there is no conclusive evidence to indicate whether it is a state- or trait-dependent phenomenon." [Abstract]

Arango V, Underwood MD, Mann JJ.
Serotonin brain circuits involved in major depression and suicide.
Prog Brain Res. 2002;136:443-53.
"Throughout his life and his work, Cajal realized the potential of the neurons he was so carefully studying and how, grouped in systems, they served the special senses and the maintenance and proper functioning of the organism. Over the past 25 years, major depression and suicide have come to be recognized as associated with alteration in serotonergic neurons and their target receptors. We examined whether prefrontal cortical (PFC) serotonin transporter sites (SERT) differ in major depression and suicide by quantitative receptor autoradiography. Clinical information was obtained by psychological autopsy. We found regionally distinct neurobiological correlates of major depression and suicide. A diffuse reduction of SERT binding throughout the dorsoventral extent of the PFC in major depression may reflect a widespread impairment of serotonergic function consistent with the range of psychopathology in major depression. The localized reduction in SERT binding in ventral PFC found in suicide victims may reflect reduced serotonin input to that brain region, underlying the predisposition to act on suicidal thoughts. It is conceivable that Cajal envisioned that psychiatric illness would be the result of "psychic neuron" pathophysiology. Today's informed psychiatrists will not be able to deny the role of the brain in the mental ailments that afflict their patients." [Abstract]

Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ.
Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims.
Neuropsychopharmacology. 2001 Dec;25(6):892-903.
"Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HT(1A) receptors in localized regions of the prefrontal cortex. In depression, there is a diffuse decrease in SERT binding throughout the dorsoventral extent of the prefrontal cortex. Serotonergic innervation of the prefrontal cortex arises predominantly from neurons in the brainstem dorsal raphe nucleus (DRN). We, therefore, examined postmortem SERT binding and mRNA expression, as well as 5-HT(1A) autoreceptor binding in the DRN of 10 matched pairs of controls and depressed suicide victims. The concentration of SERT sites, SERT mRNA, and 5-HT(1A) binding was not different between controls and suicides (p >.05). In the DRN of suicides, the volume of tissue defined by 5-HT(1A) binding was 40% smaller than controls. An index of the total number of 5-HT(1A) receptors (receptor binding x volume of receptor distribution) was 43.3% lower in the DRN of suicides, compared with controls. The suicide group had 54% fewer DRN neurons expressing SERT mRNA compared with controls. In the serotonin neurons that expressed the SERT gene, expression per neuron was greater in suicides. Less total 5-HT(1A) and SERT binding is consistent with results of in vivo studies in depression. Less feedback inhibition of serotonin DRN firing via 5-HT(1A) autoreceptors and enhancement of serotonin action due to less uptake of serotonin, is consistent with compensatory changes in response to hypofunction in depressed suicides." [Abstract]

Bligh-Glover W, Kolli TN, Shapiro-Kulnane L, Dilley GE, Friedman L, Balraj E, Rajkowska G, Stockmeier CA.
The serotonin transporter in the midbrain of suicide victims with major depression.
Biol Psychiatry. 2000 Jun 15;47(12):1015-24.
"BACKGROUND: The involvement of serotonin in depression and suicide has been proposed, because major depression is successfully treated by medications that specifically block the serotonin transporter, and there is evidence for a decrease in serotonin transporters in major depression and suicide. The midbrain dorsal raphe nucleus (DR) has been implicated as a site for diminished serotonergic activity in that suicide victims with major depression have a significant increase in serotonin-1A autoreceptors in the DR. METHODS: [(3)H]Paroxetine was used to label the serotonin transporter in the subnuclei of the DR at several rostral-to-caudal levels of the midbrain in ten pairs of suicide victims with major depression and age-matched psychiatrically normal control subjects. RESULTS: There was a significant increase in serotonin transporters in the entire DR progressing from rostral-to-caudal levels in both normal control subjects and suicide victims with major depression. At comparable rostral-to-caudal levels, there were no significant differences in [(3)H]paroxetine binding between depressed suicide victims and normal control subjects in either the entire DR or its constituent subnuclei. CONCLUSIONS: The pathophysiology of serotonin mechanisms in suicide victims with major depression does not appear to involve alterations in the binding of [(3)H]paroxetine to the serotonin transporter in the midbrain DR." [Abstract]

Lindstrom MB, Ryding E, Bosson P, Ahnlide JA, Rosen I, Traskman-Bendz L.
Impulsivity related to brain serotonin transporter binding capacity in suicide attempters.
Eur Neuropsychopharmacol. 2004 Aug;14(4):295-300.
Altered monoaminergic activity has earlier been associated with violent suicidal behaviour. In this study whole brain binding potential of the serotonin transporter (5HTT) and dopamine transporter (DAT) was measured by single photon emission computerised tomography (SPECT) in 12 patients after a serious suicide attempt and in 12 age, sex and season matched healthy controls. Clinical and temperamental assessments were analysed for possible associations with 5HTT and DAT. We found no significant 5HTT or DAT differences between patients and controls. In patients, but not in controls, there was a significant correlation between whole brain 5HTT and DAT. Impulsiveness according to the Marke Nyman Temperament (MNT) was significantly correlated to 5HTT in suicide attempters, but not in controls. Neither of the transporters could be regarded as a marker for serious suicidal behaviour. A previously discussed connection between serotonin and dopamine was replicated in this study. In suicide attempters, low 5HTT was associated with impulsivity and to some extent with depressive disorder-key factors for suicidal behaviour. [Abstract]

Mann JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango V.
A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide.
Arch Gen Psychiatry. 2000 Aug;57(8):729-38.
"BACKGROUND: Major depression and suicide are associated with fewer serotonin transporter (5-HTT) sites. The 5'-flanking promoter region of the 5-HTT gene has a biallelic insertion/deletion (5-HTTLPR). We assayed prefrontal cortical (PFC) 5-HTT binding in major depression and suicide and examine the relationship to the 5-HTTLPR allele. METHODS: Postmortem brain samples from 220 individuals were genotyped for the 5-HTTLPR polymorphism. Binding of 5-HTT was assayed by quantitative autoradiography in the PFC of a subset of subjects (n = 159). Clinical information, including DSM-III-R Axis I diagnoses, was obtained by psychological autopsy and medical chart review. RESULTS: Binding to 5-HTT was lower in the ventral PFC of suicides compared with nonsuicides and was lower throughout the PFC of subjects with a history of major depression. The 5-HTTLPR genotype was associated with major depression but not with suicide or 5-HTT binding. CONCLUSIONS: A diffuse reduction of 5-HTT binding in the PFC of individuals with major depression may reflect a widespread impairment of serotonergic function consistent with the range of psychopathologic features in major depression. The localized reduction in 5-HTT binding in the ventral PFC of suicides may reflect reduced serotonin input to that brain region, underlying the predisposition to act on suicidal thoughts. The 5-HTTLPR genotype was not related to the level of 5-HTT binding and does not explain why 5-HTT binding is lower in major depression or suicide." [Abstract]

...

Pivac N, Muck-Seler D, Barisic I, Jakovljevic M, Puretic Z.
Platelet serotonin concentration in dialysis patients with somatic symptoms of depression.
Life Sci. 2001 Apr 13;68(21):2423-33.
"Platelet serotonin (5-HT) concentration was measured in 65 male and 45 female chronic renal patients on hemodialysis (HD) with different somatic symptoms of depression (crying spells, irritability, sleep disturbance, fatigability, loss of appetite, weight loss, somatic preoccupation and loss of libido), to find out the relationship between the severity of symptoms and platelet 5-HT concentration. Male and female patients had significantly lower platelet 5-HT concentration than 62 male and 38 female healthy subjects. Gender-differences in platelet 5-HT values observed in healthy subjects were not found in patients. Platelet 5-HT concentration differed in the groups of patients with the different scores of particular somatic symptoms (loss of appetite and loss of libido), but was similar in patients with other somatic symptoms. There was no relationship between platelet 5-HT concentration and the severity of somatic symptoms, or between platelet 5-HT concentration and age of the patients. Gender-related differences in the occurrence of somatic symptoms were detected in patients with the different degrees of weight loss, somatic preoccupation and loss of libido. Our results suggest that platelet 5-HT concentration could not be used as a biological marker for the severity of somatic symptoms in chronic renal patients on HD." [Abstract]

Figueras G, Perez V, San Martino O, Alvarez E, Artigas F.
Pretreatment platelet 5-HT concentration predicts the short-term response to paroxetine in major depression. Grupo de Trastornos Afectivos.
Biol Psychiatry. 1999 Aug 15;46(4):518-24.
"BACKGROUND: A previous retrospective study revealed that a high pretreatment platelet serotonin (5-HT) concentration was associated with a low response to serotonergic antidepressants in drug-free major depressives. We have examined such a relationship in depressive patients treated with paroxetine. METHODS: Seventy-four drug-free major depressives (DSM-IV) were admitted to the study. Clinical ratings were performed and blood was drawn prior to the initiation of treatment and after 4 weeks of paroxetine (20 mg/day). The concentrations of 5-HT, 5-hydroxyindoleacetic acid, and tryptophan were determined in plasma and blood. RESULTS: Paroxetine treatment reduced platelet 5-HT to 17% of baseline after 4 weeks of treatment. Responder patients had a pretreatment platelet 5-HT concentration 22% lower than nonresponders (p < .035). Admission HAMD scores, plasma paroxetine concentration, or platelet 5-HT concentration at endpoint did not differ between responders and nonresponders. Yet, the response rate was 11% in patients with high pretreatment platelet 5-HT (> 900 ng/10(9) platelets) and 50% in those below that value (p < .004). CONCLUSIONS: These findings support that depressed patients with a high pretreatment platelet 5-HT concentration have a poor therapeutic outcome after treatment with a standard paroxetine dose. These differences may be related to the existence of molecular differences in the 5-HT transporter." [Abstract]

Shiah IS, Ko HC, Lee JF, Lu RB.
Platelet 5-HT and plasma MHPG levels in patients with bipolar I and bipolar II depressions and normal controls.
J Affect Disord. 1999 Jan-Mar;52(1-3):101-10.
"BACKGROUND: It has been suggested that platelet serotonin (5-HT) content may reflect aspects of the presynaptic reuptake of 5-HT, while plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels may provide an index of central noradrenergic function. METHODS: In order to determine if there is a biological distinction in 5-HT or noradrenergic function within bipolar I and bipolar II depressions, we measured levels of platelet 5-HT and plasma MHPG in 12 patients with bipolar I depression, 12 patients with bipolar II depression, and 20 normal healthy controls. All subjects were medication free for at least 4 weeks prior to the study. RESULTS: There was a trend towards higher platelet 5-HT in bipolar I or II depressions when compared to normal controls, whereas there was no difference in platelet 5-HT levels between bipolar I and II depressed patients. When bipolar I and II patients were pooled, there was a significant increase in platelet 5-HT levels in bipolar depressives compared to normal controls, and there was a trend towards a weak positive correlation between platelet 5-HT and 21-item HAMD scores in the patient group. In contrast, there was no difference in plasma MHPG levels between the three groups. LIMITATIONS: This study was limited to a small sample size, single point sampling and did not match seasons. CONCLUSIONS: Our findings did not provide supportive evidence for a distinctive 5-HT or noradrenergic function within bipolar I and bipolar II depressions. However, the finding of increased platelet 5-HT levels in bipolar depressed patients compared to normal controls is consistent with the results of previous studies, and may suggest an increase in presynaptic 5-HT reuptake, presumably resulting from diminished synaptic 5-HT availability in this condition." [Abstract]

Lestra C, d'Amato T, Ghaemmaghami C, Perret-Liaudet A, Broyer M, Renaud B, Dalery J, Chamba G.
Biological parameters in major depression: effects of paroxetine, viloxazine, moclobemide, and electroconvulsive therapy. Relation to early clinical outcome.
Biol Psychiatry. 1998 Aug 15;44(4):274-80.
"BACKGROUND: Clinical and pharmacologic studies report a relative or absolute serotonergic deficiency in major depression; however, the variability of clinical characteristics of illness has led to controversial results. In the present work, we looked for a possible relationship between i) biochemical values that indirectly reflect aminergic neurons activity and clinical characteristics and ii) their evolution and the early clinical outcome under antidepressive therapies (ATs). METHODS: Platelet serotonin content, platelet monoamine oxydase activity, and urinary biopterins were measured in 27 depressed patients before and during four different ATs (paroxetine, viloxazine, moclobemide, or electroconvulsive therapy). Depressive symptomatology and its evolution under ATs were quantified using three clinical rating scales. RESULTS: A severe symptomatology, high serotonin (5-HT) platelet content, and high or low urinary B could represent risk factors leading to a smaller or delayed response to an AT. Furthermore, the early improvement under ATs was negatively correlated to pretreatment 5-HT platelet content. CONCLUSIONS: Determination of 5-HT level could be useful in the choice of an AT." [Abstract]

Muck-Seler D, Jakovljevic M, Pivac N.
Platelet 5-HT concentrations and suicidal behaviour in recurrent major depression.
J Affect Disord. 1996 Jun 20;39(1):73-80.
"Platelet 5-HT concentrations were determined in 84 male and 82 female psychotic and non-psychotic depressed inpatients with various degrees of suicidal behaviour, and in 175 healthy controls. Psychotic patients had higher platelet 5-HT concentrations than non-psychotic depressed patients and healthy controls. A sex difference, i.e., lower platelet 5-HT concentrations in females was found in healthy controls, depressed patients, non-psychotic patients and non-suicidal depressed patients. A negative relationship was shown between platelet 5-HT concentrations and suicidal behaviour. The lowest platelet 5-HT concentrations were associated with the most pronounced suicidal behaviour (with suicidal attempts and with the acts of suicide). The results suggest that the differences in platelet 5-HT concentrations found in depressed patients might be used as a biological marker for suicidal behaviour." [Abstract]

Mann JJ, McBride PA, Anderson GM, Mieczkowski TA.
Platelet and whole blood serotonin content in depressed inpatients: correlations with acute and life-time psychopathology.
Biol Psychiatry. 1992 Aug 1;32(3):243-57.
"Platelet or whole blood serotonin content did not differ significantly in patients with major depression compared to healthy controls, but within the patient group, platelet serotonin levels correlated negatively with severity of depression (r = -0.49, p = 0.007). Levels were 39% lower in patients who had made a suicide attempt compared to nonattempter patients (47.2 +/- 27.3 versus 77.6 +/- 41.7 ng/10(8) platelets, p = 0.04). Conversely, comorbid borderline personality disorder (85.3 +/- 41.5 ng/10(8) platelets) was associated with 31% greater platelet serotonin content than nonborderline patients (58.9 +/- 31.1 ng/10(8) platelets) and 27% greater than healthy controls (62.4 +/- 19.8 ng/10(8) platelets). A pronounced seasonal variation in whole blood and platelet serotonin content was found in both patients and controls, largely due to lower levels in summer. Excluding cases tested in the summer abolished the statistically significant differences in patients with and without comorbid borderline personality disorder (BPD). Nevertheless, BPD attempters had lower serotonin levels than BPD nonattempters but higher serotonin levels than non-BPD attempters. Current hostility and a life-time history of aggression were positively correlated with platelet serotonin content (r = 0.44, p = 0.04 and r = 0.41, p = 0.06). This study provides evidence for an association between lower platelet serotonin content and depression and suicidal behavior, and association of higher platelet serotonin content and comorbid borderline personality disorder and behavior traits such as aggressivity." [Abstract]

Muck-Seler D, Jakovljevic M, Deanovic Z.
Effect of antidepressant treatment on platelet 5-HT content and relation to therapeutic outcome in unipolar depressive patients.
J Affect Disord. 1991 Nov;23(3):157-64.
"Platelet 5-HT levels and scores on the 17-item Hamilton Rating Scale for Depression (HRS) were studied in patients with unipolar depression before and after antidepressant treatment. Before treatment there were no differences in platelet 5-HT values or in HRS scores between patients who showed a good and a poor therapeutic response. Repeated administration of 5-HT uptake inhibitors (amitriptyline, clovoxamine, fluvoxamine) for 28 days markedly decreased platelet 5-HT levels. Chronic treatment with trazodone or maprotiline (weak inhibitors of platelet 5-HT uptake) produced no changes in platelet 5-HT levels. No significant correlation was observed between platelet 5-HT concentrations and the HRS scores before or during treatment. The findings suggest that the changes in platelet 5-HT levels after antidepressant treatment are mainly due to the effects of antidepressants on the 5-HT uptake system." [Abstract]

Guicheney P, Leger D, Barrat J, Trevoux R, De Lignieres B, Roques P, Garnier JP, Boyer P, Grenier J, Dreux C, et al.
Platelet serotonin content and plasma tryptophan in peri- and postmenopausal women: variations with plasma oestrogen levels and depressive symptoms.
Eur J Clin Invest. 1988 Jun;18(3):297-304.
"Platelet serotonin content was measured by high pressure liquid chromatography in 56 peri- and postmenopausal women, in order to study variations of this parameter with hormonal status and depressive mood symptoms. Clinical symptoms were assessed by a self-report depression symptom scale (CES-D of NIMH). Thirty-eight women with a score of 16 or more were considered as presenting depressive symptoms (mean score +/- SD = 28.8 +/- 10.5), while the others formed the control group (n = 18, score = 4.4 +/- 4.2). Platelet serotonin contents were significantly lower in the 'depressed' group (0.302 +/- 0.010 vs. 0.366 +/- 0.020 nmol 10(-8) platelets, means + SEM, P less than 0.001 by Mann-Whitney U-test). In 'depressed' women who had been treated for one or more depressive episodes, platelet 5-HT contents (0.283 +/- 0.023, n = 18, P less than 0.01) were significantly lower with respect to controls. In patients without previous episodes of depression, serotonin expressed in nmol 10(-8) platelets did not differ significantly from controls but serotonin expressed in nmol ml-1 of blood was slightly lower than control values (0.890 +/- 0.085, n = 20 vs. 1.088 +/- 0.090 nmol ml-1, n = 18, P less than 0.02). Platelet serotonin content was positively correlated to plasma oestrone and oestradiol concentrations among the control group but not in the 'depressed' group." [Abstract]

Barisic I, Pivac N, Muck-Seler D, Jakovljevic M, Sagud M.
Comorbid depression and platelet serotonin in hemodialysis patients.
Nephron Clin Pract. 2004;96(1):c10-4.
BACKGROUND/AIM: Comorbid depression often occurs in chronic renal failure patients on hemodialysis (HD). Reduced serotonin (5-HT) function is implicated in the pathophysiology of depression. METHODS: Comorbid depression and different clusters of depressive symptoms were assessed in 79 male HD patients and 35 male depressed psychiatric patients. Platelet 5-HT concentration (a peripheral model for the central serotonergic neurons) was determined in all patients and 80 male healthy controls. RESULTS: Comorbid depression occurred in 50 out of 79 HD patients. Depressed psychiatric patients and depressed HD patients had higher scores of anxiety, retardation, and cognitive symptoms than nondepressed HD patients. Platelet 5-HT concentration was lower in depressed or nondepressed HD patients than in healthy controls, or in depressed patients. Higher platelet 5-HT content was found in depressed psychiatric patients with depressive clusters than in all other patients. Among HD patients, anxious HD patients had a higher platelet 5-HT concentration than HD patients without anxiety symptoms. CONCLUSIONS: Comorbid depression occurred in 63% of HD patients. Dialyzed patients had decreased platelet 5-HT concentration, regardless of the occurrence of comorbid depression. Higher platelet 5-HT concentration was related to anxiety symptoms in HD patients. Our data suggest that platelet 5-HT concentration might be a suitable marker for anxiety symptoms in dialyzed patients. [Abstract]

Bianchi M, Moser C, Lazzarini C, Vecchiato E, Crespi F.
Forced swimming test and fluoxetine treatment: in vivo evidence that peripheral 5-HT in rat platelet-rich plasma mirrors cerebral extracellular 5-HT levels, whilst 5-HT in isolated platelets mirrors neuronal 5-HT changes.
Exp Brain Res. 2002 Mar;143(2):191-7. Epub 2002 Jan 24.
"Low levels of central serotonin (5-HT) have been related to the state of depression, and 5-HT is the major target of the newer antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs). Neurons and platelets display structural and functional similarities, so that the latter have been proposed as a peripheral model of central functions. In particular, in blood more than 99% of 5-HT is contained in platelets, so that one could consider changes in 5-HT levels in platelets as a mirror of changes in central 5-HT. Here, this hypothesis has been studied via the analysis of the influence of: (1) the forced swimming test (FST, which has been proved to be of utility to predict the clinical efficacy of antidepressants in rodents) and (2) treatment with the SSRI fluoxetine upon 5-HT levels monitored in brain regions and in peripheral platelets by means of electrochemical in vivo and ex vivo measurements. The results obtained confirm that the FST increases immobility; furthermore they show a parallel and significant decrease in cerebral (brain homogenate) and peripheral (in platelet-rich plasma, PRP) voltammetric 5-HT levels following the FST in naive rats. In addition, subchronic treatment with fluoxetine was followed by a significant increase in 5-HT levels in PRP, while the same SSRI treatment performed within the FST resulted in a decrease in the 5-HT levels in PRP. However, this decrease was inferior to that observed without SSRI treatment. These data suggest that there is an inverse relationship between immobility and the levels of 5-HT in PRP and that these peripheral 5-HT levels are sensitive to: (1) the FST, (2) the treatment with fluoxetine and (3) the combination of both treatments, i.e. SSRI + FST. It has been reported that SSRI treatment at first inhibits the 5-HT transporter in brain, resulting in increased extracellular 5-HT, while following sustained SSRI treatments decreased intracellular levels of central 5-HT were observed. Accordingly, the present data show that the initial block of 5-HT reuptake is revealed by the selective increase in 5-HT levels (extracellular content) measured in PRP (not in insulated platelets, IPs) the 1st day of fluoxetine treatment. The initial action of this SSRI upon the 5-HT transporter in brain has also been confirmed by in vivo voltammetric data showing selective increase in the serotonergic signal following local injection of fluoxetine into the brain region studied. Successively, the major effect monitored is a decrease in 5-HT levels, which is more evident in IPs than in PRP. However, it is known that following 2 weeks treatment with an SSRI, 5-HT autoreceptors are desensitized and the serotonin synthesis is restored, together with the intracellular 5-HT levels. The present data showing that the levels of 5-HT in IPs tend to return to control values 12 days after the beginning of chronic fluoxetine treatment suggest that 5-HT levels in IPs (intracellular environment) mirror the influence of SSRI treatment upon the central 5-HT system. On the other hand, at day 12 of the chronic fluoxetine treatment, 5-HT content remains low in PRP. Similarly, low levels of 5-HT have been monitored in brain homogenate of rats chronically treated with fluoxetine. This would support the similarity between PRP preparation and brain homogenate as in both cases cells are disrupted by sample preparation. In conclusion this work supports the literature in proposing platelets as a peripheral model of central functions. In particular, the present data support the idea that peripheral 5-HT platelet levels can reflect the state of the central 5-HT system in conditions of depression. Furthermore, the main outcome of this study is that PRP may mirror central extracellular 5-HT levels, whilst IPs mirror neuronal 5-HT changes." [Abstract]

Blardi P, De Lalla A, Leo A, Auteri A, Iapichino S, Di Muro A, Dell'Erba A, Castrogiovanni P.
Serotonin and fluoxetine levels in plasma and platelets after fluoxetine treatment in depressive patients.
J Clin Psychopharmacol. 2002 Apr;22(2):131-6.
"Depression is a mood disorder characterized by complex alterations of neurotransmitters such as serotonin, norepinephrine, and dopamine. In particular, there is substantial evidence of abnormalities in serotonin neurotransmission. Peripheral parameters of serotoninergic transmission, such as the 5-hydroxytryptamine content of plasma and platelets, have been used to identify biochemical alterations related to depression. In recent years, these parameters have also been used to examine the mechanism of action of antidepressive drugs such as the selective serotonin reuptake inhibitors.This study investigated the interaction between the plasma and platelet levels of fluoxetine and serotonin after fluoxetine administration to depressed patients. Twelve patients affected by major depression (according to the DSM-IV criteria) received a single oral dose of fluoxetine in the morning: 5 mg in the first 5 days, 10 mg from day 6 to day 10, and 20 mg from day 11 to day 40. Blood samples were collected at 0, 7, 10, and 24 hours after drug administration on the day 1 of fluoxetine 5 mg and on the 1st and the 30th day of fluoxetine 20 mg (days 11 and 40 of treatment, respectively).Plasma fluoxetine and serotonin levels increased after drug administration, reaching the highest levels on the 30th day of fluoxetine 20 mg. Fluoxetine levels were also detectable in platelets, with a time variation similar to plasma values. Platelet serotonin levels decreased after drug administration, and the lowest values were observed on the 30th day of fluoxetine 20 mg." [Abstract]

Lima L, Urbina M.
Serotonin transporter modulation in blood lymphocytes from patients with major depression.
Cell Mol Neurobiol. 2002 Dec;22(5-6):797-804.
"1. Serotonin is a neurotransmitter in the central nervous system which has been implicated in the aetiology and pathogenesis of affective disorders. The serononergic system also plays several roles in the immune system through the expression of a number of its receptor subtypes in the immune cells. 2. Following release serotonin is inactivated by reuptake into neurons and other cells by a specific serotonin sodium and chloride-dependent transporter molecule, whose structure has been elucidated. 3. Measurement [3H]paroxetine binding showed that human lymphocytes contain a high-affinity serotonin transporter. 4. To assess the serotonin function in major depression, we investigated serotonin transporter density in blood lymphocytes from patients with this disorder and selected according to the interview of the American Psychiatric Association. 5. Patients were divided into two groups and treated with two different antidepressant drugs, one group receiving fluoxetine, a selective serotonin reuptake inhibitor, and another mirtazapine, an antagonist of alpha2-adrenergic auto and heteroreceptors, for a period of 6 weeks. 6. Blood samples were obtained before and after the treatment, lymphocytes were isolated by Ficoll/Hypaque gradient, subjected to differential adhesion to plastic, and cell membranes were prepared for binding assay of [3H]paroxetine. 7. Lymphocytes serotonin transporter number was significantly reduced, while the affinity was unchanged, in patients with major depression disorder as compare to controls. 8. In addition, there was a partial recovery in lymphocytes serotonin (5HT) transporter number in the period posterior to the antidepressants administration, accompanied with clinical and depression rating scales improvement. Serotonin was determined in platelet-poor plasma and in lymphocytes before and after drugs administration, showing a significant decrease in the patients treated compared to untreated and controls. 9. These results are evidence of the potential interaction between the nervous and immune systems. The mechanisms underlying this interaction are under study, and might be related to modifications in the expression or function of the serotonin transporters in lymphocytes of depressed patients." [Abstract]

Fajardo O, Galeno J, Urbina M, Carreira I, Lima L.
Serotonin, serotonin 5-HT(1A) receptors and dopamine in blood peripheral lymphocytes of major depression patients.
Int Immunopharmacol. 2003 Sep;3(9):1345-52.
There are increasing evidences of cell markers present in the immune and the nervous systems. These include neurotransmitter receptors and transporters. Serotonin receptor subtypes are related to depression and also have been shown to be present in certain cells of the immune system. In the present report, we determined the presence of 5-HT(1A) receptors by the binding of the selective agonist 8-hydroxy-2-(di-n-propyl-amino)tetralin in lymphocytes of peripheral blood isolated by Ficoll/Hypaque gradients from controls and depressed patients. The capacity of these receptors was around 24 fmol/10(6) cells in both groups of subjects, without significant difference among them. The affinity was in the nM range and either differ between controls and patients. Serotonin, 5-hydroxyindoleacetic acid, dopamine and 3,4-dihydroxyphenylacetic acid were determined by HPLC with electrochemical detector. There were no significant differences between controls and major depression patients in the values obtained for rich and poor platelet plasma or in the isolated cells. However, there was a reduction in serotonin turnover rate indicated by an increase in the ratio serotonin/5-hydroxyindoleacetic acid, but not in that of dopamine, in lymphocytes of major depression patients. Thus, there is a serotonergic dysfunction in immune circulating cells of major depression patients, without changes in the number of 5-HT(1A) receptors, although the coupling of these receptors to transduction mechanisms could be affected and may be related to the alteration of 5-HT turnover rate. [Abstract]

Tafet GE, Idoyaga-Vargas VP, Abulafia DP, Calandria JM, Roffman SS, Chiovetta A, Shinitzky M.
Correlation between cortisol level and serotonin uptake in patients with chronic stress and depression.
Cogn Affect Behav Neurosci. 2001 Dec;1(4):388-93.
"In a recent study (Tafet, Toister-Achituv, & Shinitzky, 2001), we demonstrated that cortisol induces an increase in the expression of the gene coding for the serotonin transporter, associated with a subsequent elevation in the uptake of serotonin. This stimulatory effect, produced upon incubation with cortisol in vitro, was observed in peripheral blood lymphocytes from normal subjects. In the present work we investigated the cortisol-induced increase in serotonin uptake in lymphocytes from hypercortisolemic patients, including subjects with major depressive disorder (n = 8), and subjects with generalized anxiety disorder (n = 12), in comparison with a control group of normal healthy subjects (n = 8). A significant increase in serotonin uptake (+37% + 14, M + SD) was observed in the control group, whereas neither the generalized anxiety disorder nor the major depression group exhibited changes in serotonin uptake upon incubation with cortisol. It is likely that under chronic stress or depression, the capacity for increase in serotonin transporter has reached its limit due to the chronically elevated blood cortisol level. The physiological and diagnostic implications of this observation are discussed." [Abstract]

Roy A.
Suicidal behavior in depression: relationship to platelet serotonin transporter.
Neuropsychobiology. 1999;39(2):71-5.
"OBJECTIVE: Suicidal behavior in depressed patients is associated with low central serotonin. Thus, platelet serotonin uptake in relation to suicidal behavior in depression was examined. METHODS: Depressed patients who had never attempted suicide (n = 23) were compared with depressed patients who had never attempted suicide (n = 26) and normal controls (n = 71) for platelet serotonin uptake. RESULTS: Depressed patients who had a lifetime history of a suicide attempt had a significantly greater apparent Michaelis constant (Km) of platelet serotonin uptake than either depressed patients who had never attempted suicide or controls. Patients rated high for current suicidal ideation at the index admission had significantly higher Km values than patients rated low. Also, patients who reattempted or committed suicide during a 5-year follow-up period had significantly higher Km values than controls. Among women patients who had attempted suicide there was a significant correlation between extrapunitive hostility scores and Km values. CONCLUSION: The serotonin transporter warrants further study in relation to suicidal behavior in depression." [Abstract]

Sallee FR, Hilal R, Dougherty D, Beach K, Nesbitt L.
Platelet serotonin transporter in depressed children and adolescents: 3H-paroxetine platelet binding before and after sertraline.
J Am Acad Child Adolesc Psychiatry. 1998 Jul;37(7):777-84.
"OBJECTIVE: To evaluate serotonin transporter protein (5HTPR) binding in platelets from children and adolescents with major depression (MDD) compared to normal controls using the selective ligand 3H-paroxetine. METHOD: Children and adolescents with MDD (n = 24) defined by DSM-III-R criteria and normal controls (n = 22) were compared by platelet 5HTPR kinetic analysis with the hypothesis that 5HTPR is reduced in MDD. A subset of MDD subjects (n = 18) continued to participate in a fixed-dose, open-label sertraline trial for 6 weeks followed by drug-free washout and repeated 5HTPR analysis. RESULTS: Sex, prepubertal status, and age had no effect on 5HTPR. Medication-free MDD subjects differed from controls in reduced binding capacity (Bmax) (p < .001). Sertraline therapy decreased binding affinity from baseline non-selectively (p < .05), and Bmax elevation from baseline was associated with nonresponse and suicide attempt history. CONCLUSION: Earlier literature in this population is replicated with regard to reduced platelet 5HTPR Bmax in MDD. Findings support a continuum of 5HTPR involvement in MDD across the developmental spectrum." [Abstract]

D'Hondt P, Maes M, Leysen JE, Gommeren W, Scharpe S, Cosyns P.
Binding of [3H]paroxetine to platelets of depressed patients: seasonal differences and effects of diagnostic classification.
J Affect Disord. 1994 Sep;32(1):27-35.
"[3H]Paroxetine is a more reliable ligand for studying the serotonin (5-HT) transporter complex than [3H]imipramine. The present study investigates [3H]paroxetine binding to platelets in 54 depressed in-patients (18 minor, 16 simple major and 20 melancholic depressed patients) and 16 healthy controls. There were no significant differences in maximal number of binding sites between depressed subjects and normal controls. There was no correlation between [3H]paroxetine binding to platelet membranes and severity of depression. [3H]Paroxetine binding to platelets was significantly higher in spring than in summer, fall and winter." [Abstract]

...

 

Perez V, Bel N, Celada P, Ortiz J, Alvarez E, Artigas F.
Relationship between blood serotonergic variables, melancholic traits, and response to antidepressant treatments.
J Clin Psychopharmacol. 1998 Jun;18(3):222-30.
"The relationship between peripheral serotonergic variables, melancholic traits, and clinical improvement after antidepressant treatment was examined in 83 drug-free major depressive patients. Plasma serotonin (5-HT) concentrations was lower in untreated melancholic patients (1.00 +/- 0.11 vs. 1.84 +/- 0.28 ng/mL, p < 0.008; N = 40 and 43, respectively). A tendency was observed for plasma 5-hydroxyindoleacetic acid (p < 0.06), whereas platelet 5-HT and plasma tryptophan did not differ between groups. After blood sampling and clinical ratings, treatment began with fixed doses of 5-HT uptake inhibitors (clomipramine or fluvoxamine), monoamine oxidase inhibitors, or tianeptine, a 5-HT uptake enhancer. There was no significant difference in response rates between patients with and without melancholic traits. The relationship between the clinical response at 6 weeks (>50% reduction of baseline Hamilton score) and the pretreatment values of biochemical variables was examined. Responders had a lower pretreatment platelet 5-HT (530 +/- 36 vs. 664 +/- 50 ng/10(9) platelets, p < 0.03; N = 44 and 39, respectively). Patients with a platelet 5-HT concentration above 800 ng/10(9) platelets had a lower response rate than those below this value (p < 0.003). This difference was maximal in the subgroup of patients treated with 5-HT uptake inhibitors (N = 49). In this subgroup, the response rates of patients with 5-HT concentrations below and above the cutoff point were, respectively, 70% and 17% (p < 0.001). A pretreatment platelet 5-HT value above 800 ng/10(9) platelets had a predictive value for a negative response of 92%. These results suggest the presence of biochemical differences in the peripheral serotonergic system between melancholic and nonmelancholic patients. The inverse relationship between the pretreatment platelet 5-HT content and clinical response may be useful in the investigation of the relationship between the 5-HT system and antidepressant response." [Abstract]

Pivac N, Jakovljevic M, Muck-Seler D, Brzovic Z.
Hypothalamic-pituitary-adrenal axis function and platelet serotonin concentrations in depressed patients.
Psychiatry Res. 1997 Dec 5;73(3):123-32.
"Plasma cortisol and platelet serotonin (5-hydroxytryptamine, 5-HT) concentrations were determined in 39 male psychotic and 39 male non-psychotic depressed inpatients, and in 69 male healthy control subjects. Psychotic or non-psychotic depressed patients had higher predexamethasone plasma cortisol levels than found in the control group. After the dexamethasone suppression test (DST), psychotic and non-psychotic depressed patients were subdivided into suppressors and non-suppressors. Psychotic and non-psychotic patients had significantly different platelet 5-HT concentrations among themselves and compared with the control group. However, there was no significant correlation between plasma cortisol levels and platelet 5-HT concentrations. Dexamethasone administration did not affect platelet 5-HT concentrations within subtypes of depressed patients. Abnormal cortisol suppression after the DST occurred more frequently in psychotic than in non-psychotic patients. Platelet 5-HT and plasma cortisol concentrations were decreased in patients with pronounced suicidal behaviour. Our results suggest that plasma cortisol and platelet 5-HT concentrations might serve as independent biological markers for different subtypes of depression." [Abstract]

Jakovljevic M, Muck-Seler D, Pivac N, Ljubicic D, Bujas M, Dodig G.
Seasonal influence on platelet 5-HT levels in patients with recurrent major depression and schizophrenia.
Biol Psychiatry. 1997 May 15;41(10):1028-34.
"The influence of seasons on platelet serotonin (5-HT) concentration was determined in 88 unipolar depressed and 117 schizophrenic male inpatients, and 90 normal male controls. Platelet 5-HT concentrations showed moderate, but insignificant intragroup seasonal variations in healthy controls and in the groups of depressed (psychotic and nonpsychotic) and schizophrenic (positive and negative) patients. In spring, platelet 5-HT concentrations were higher in schizophrenic patients than in normal controls or in depressed patients, while in other seasons platelet 5-HT concentrations were not significantly different between the groups. Higher platelet 5-HT concentrations were detected in psychotic when compared to nonpsychotic depressed patients in summer, fall, and winter. Increased platelet 5-HT concentrations observed in schizophrenic patients with positive symptoms clearly separated these patients from patients with negative schizophrenia, especially in spring, summer, and fall. Our results indicate the necessity to match patients with regard to the season of the sampling, and to divide depressed and schizophrenic patients into subtypes." [Abstract]

Muck-Seler D, Jakovljevic M, Deanovic Z.
Platelet serotonin in subtypes of schizophrenia and unipolar depression.
Psychiatry Res. 1991 Aug;38(2):105-13.
"In subtypes of schizophrenia and unipolar depression, both increased and decreased levels of platelet serotonin were found. Hyperserotonemia was usually observed in patients with psychotic features (i.e., in paranoid schizophrenia and psychotic depression). Hyposerotonemia, although less common than hyperserotonemia, was present in nonparanoid schizophrenia and nonpsychotic depression (i.e., in patients without psychotic symptoms). A sex difference in platelet monoamine oxidase activity was observed among healthy subjects, but not among schizophrenic patients. The activity of platelet monoamine oxidase in paranoid and nonparanoid schizophrenic patients did not differ from that in healthy subjects. The findings in this study suggest that biological differences between subtypes of unipolar depression or schizophrenia might depend upon the presence of psychotic symptoms." [Abstract]

Ko HC, Lu RB, Shiah IS, Hwang CC.
Plasma free 3-methoxy-4-hydroxyphenylglycol predicts response to fluoxetine.
Biol Psychiatry. 1997 Apr 1;41(7):774-81.
"This study was designed to investigate the relationship between platelet serotonin (5-HT) and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) measures in depressed outpatients obtained from the same patient with unipolar depression during the pretreatment period and subsequent response to 6 weeks of treatment with either fluoxetine or maprotiline. Compared to the nonresponder group, the fluoxetine responders showed significantly higher pretreatment levels of MHPG, but no difference in pretreatment 5-HT levels. There were no significant differences in either 5-HT or MHPG levels between maprotiline responders and nonresponders. As to posttreatment levels, there were no between-group differences in 5-HT or MHPG between responders and nonresponders to either fluoxetine or maprotiline. When the relationships between changes in 5-HT or MHPG levels and treatment response were examined, 5-HT values showed a marked decrease in both fluoxetine responders and nonresponders, but no significant changes were found in the maprotiline treatment groups. On the other hand, MHPG levels in the fluoxetine nonresponders tended to increase (borderline significance), whereas the MHPG levels for fluoxetine responders and maprotiline responders and nonresponders were unaffected from pre- to posttreatment. Pretreatment levels of plasma free MHPG appear to predict response to fluoxetine." [Abstract]

Karege F, Widmer J, Bovier P, Gaillard JM.
Platelet serotonin and plasma tryptophan in depressed patients: effect of drug treatment and clinical outcome.
Neuropsychopharmacology. 1994 May;10(3):207-14.
"Platelet serotonin and plasma tryptophan were studied in healthy subjects and in depressed patients before and during their antidepressant drug treatment. Before treatment, mean platelet serotonin level was normal in depressed patients compared with healthy subjects while a significant decrease in patients' plasma TRP was noted (t = 6.0, p < .001). The concentrations of platelet 5-HT level did not correlate with either plasma TRP or with clinical variables, that is, AMDP depression and AMDP anxiety scores. Antidepressant drugs treatment decreased platelet 5-HT level (ANOVA F = 8.27, p < .001) whatever the clinical outcome of the patient, whereas the changes observed in plasma TRP were positively related to the mood state change. These results suggest that platelet serotonin could be a good pharmacological model but has no relevance concerning the mood state." [Abstract]

Celada P, Perez J, Alvarez E, Artigas F.
Monoamine oxidase inhibitors phenelzine and brofaromine increase plasma serotonin and decrease 5-hydroxyindoleacetic acid in patients with major depression: relationship to clinical improvement.
J Clin Psychopharmacol. 1992 Oct;12(5):309-15.
"We have examined the effects of two monoamine oxidase (MAO) inhibitors with different mechanisms of action--phenelzine and brofaromine--on peripheral serotonergic (5-hydroxytryptamine [5-HT]) measures, sensitive to the inhibition of MAO-A (intra- and extracellular 5-HT and related metabolites in blood). Both drugs increased the concentration of 5-HT in platelet-free plasma (254%, p less than 0.001) in patients with depressive illness (DSM-III-R) after 6 weeks of daily treatment. Platelet 5-HT was also increased significantly in both drug treatment groups but more marked in the patient group treated with phenelzine. The acid/amine ratio at 6 weeks was 30% of pretreatment values (p less than 0.000) and individual variability correlated significantly with the Hamilton Rating Scale for Depression. Plasma 5-HT increased more markedly in responders than in nonresponders and a significant inverse relationship surfaced between plasma 5-HT and the Hamilton Rating Scale for Depression. The results support other reports of comparable antidepressant efficacy for brofaromine and phenelzine, both inhibitors of MAO-A in humans. The consistent relationship we found between the biochemical and clinical changes again suggests and supports a key role of 5-HT in the antidepressant effect of these MAO inhibitors." [Abstract]

Quintana J.
Platelet serotonin and plasma tryptophan decreases in endogenous depression. Clinical, therapeutic, and biological correlations.
J Affect Disord. 1992 Feb;24(2):55-62.
"Platelet serotonin (5-HT) and plasma tryptophan (free and total) levels were measured in 25 unmedicated depressed patients and in 25 age- and sex-matched healthy controls. The same parameters were determined in the patients after 3 weeks and 2 months of imipramine treatment. Comparisons between patients and control values showed a significant decrease in total plasma tryptophan and platelet 5-HT in unmedicated patients. During treatment, the clinical condition of the patients improved, while plasma tryptophan and platelet 5-HT values normalized after 3 weeks and 2 months, respectively. Clinical status, plasma tryptophan, platelet 5-HT, as well as other biological parameters determined concurrently in the patients, such as platelet monoamine oxidase (MAO), 5-HT uptake, and imipramine binding were compared in search of significant correlations: neither the individual values of any of them nor the magnitude of their changes at any given stage or interval of the study, respectively, were found significantly correlated. These results suggest that a series of 5-HT-related biological parameters are altered in endogenous depression and tend to normalize with imipramine treatment leading to clinical recovery. Within individuals, those parameters are not correlated, suggesting that both the effect of the drug and clinical improvement affect them separately." [Abstract]

Sarrias MJ, Artigas F, Martinez E, Gelpi E, Alvarez E, Udina C, Casas M.
Decreased plasma serotonin in melancholic patients: a study with clomipramine.
Biol Psychiatry. 1987 Dec;22(12):1429-38.
"Eighteen unmedicated patients suffering from major depressive disorder with melancholia (DSM-III) were examined for abnormalities in peripheral serotonin (5-HT) and related metabolites. Serotonin in platelet-free plasma and in platelets from melancholics was significantly reduced to 30% and 60% of their respective control values. Plasma 5-hydroxyindoleacetic acid was also found to be reduced, but not significantly. Other plasma compounds related to 5-HT (indoleacetic acid, total tryptophan, and free tryptophan) were found to be unchanged in these patients. Of all variables, only platelet 5-HT was affected while patients were on clomipramine (CIM) treatment. After 2 weeks on CIM (100-150 mg/day, orally), platelet 5-HT was reduced to 8% of pretreatment values, but plasma 5-HT did not change and continued to be reduced upon clinical recovery. The existence of a distinct pool of plasma 5-HT that is clearly independent of the platelet pool is indicated by the differences observed in plasma and platelet 5-HT during CIM treatment, as well as by previous data from this laboratory. The very marked decrease in plasma 5-HT levels may be in accord with the central nervous system changes reported in depression and suggests the possibility of using plasma 5-HT as a peripheral indicator of abnormal serotonin function in melancholia." [Abstract]