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.
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]
Antidepressant binding: implications for the mode of action and
the biology of depression.
Prog Neuropsychopharmacol Biol
"(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]
V, Underwood MD, Mann JJ.
Serotonin brain circuits involved in major
depression and suicide.
Prog Brain Res. 2002;136:443-53.
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]
V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ.
1A receptors, serotonin transporter binding and serotonin transporter mRNA expression
in the brainstem of depressed suicide victims.
"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]
W, Kolli TN, Shapiro-Kulnane L, Dilley GE, Friedman L, Balraj E, Rajkowska G,
The serotonin transporter in the midbrain of suicide
victims with major depression.
Biol Psychiatry. 2000 Jun
"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]
MB, Ryding E, Bosson P, Ahnlide JA, Rosen I, Traskman-Bendz L.
related to brain serotonin transporter binding capacity in suicide attempters.
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]
JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango
A serotonin transporter gene promoter polymorphism (5-HTTLPR)
and prefrontal cortical binding in major depression and suicide.
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]
N, Muck-Seler D, Barisic I, Jakovljevic M, Puretic Z.
concentration in dialysis patients with somatic symptoms of depression.
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]
G, Perez V, San Martino O, Alvarez E, Artigas F.
5-HT concentration predicts the short-term response to paroxetine in major depression.
Grupo de Trastornos Afectivos.
Biol Psychiatry. 1999 Aug
"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
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.
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]
C, d'Amato T, Ghaemmaghami C, Perret-Liaudet A, Broyer M, Renaud B, Dalery J,
Biological parameters in major depression: effects of paroxetine,
viloxazine, moclobemide, and electroconvulsive therapy. Relation to early clinical
Biol Psychiatry. 1998 Aug 15;44(4):274-80.
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]
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]
JJ, McBride PA, Anderson GM, Mieczkowski TA.
Platelet and whole blood
serotonin content in depressed inpatients: correlations with acute and life-time
Biol Psychiatry. 1992 Aug 1;32(3):243-57.
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]
D, Jakovljevic M, Deanovic Z.
Effect of antidepressant treatment
on platelet 5-HT content and relation to therapeutic outcome in unipolar depressive
J Affect Disord. 1991 Nov;23(3):157-64.
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
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
"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]
I, Pivac N, Muck-Seler D, Jakovljevic M, Sagud M.
and platelet serotonin in hemodialysis patients.
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
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.
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]
P, De Lalla A, Leo A, Auteri A, Iapichino S, Di Muro A, Dell'Erba A, Castrogiovanni
Serotonin and fluoxetine levels in plasma and platelets after
fluoxetine treatment in depressive patients.
J Clin Psychopharmacol.
"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.
modulation in blood lymphocytes from patients with major depression.
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]
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.
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]
GE, Idoyaga-Vargas VP, Abulafia DP, Calandria JM, Roffman SS, Chiovetta A, Shinitzky
Correlation between cortisol level and serotonin uptake in patients
with chronic stress and depression.
Cogn Affect Behav Neurosci.
"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]
Suicidal behavior in depression:
relationship to platelet serotonin transporter.
"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]
FR, Hilal R, Dougherty D, Beach K, Nesbitt L.
transporter in depressed children and adolescents: 3H-paroxetine platelet binding
before and after sertraline.
J Am Acad Child Adolesc Psychiatry.
"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
Binding of [3H]paroxetine to platelets of depressed patients:
seasonal differences and effects of diagnostic classification.
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.
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
Pivac N, Jakovljevic M, Muck-Seler D, Brzovic Z.
axis function and platelet serotonin concentrations in depressed patients.
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]
M, Muck-Seler D, Pivac N, Ljubicic D, Bujas M, Dodig G.
influence on platelet 5-HT levels in patients with recurrent major depression
Biol Psychiatry. 1997 May 15;41(10):1028-34.
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]
D, Jakovljevic M, Deanovic Z.
Platelet serotonin in subtypes of schizophrenia
and unipolar depression.
Psychiatry Res. 1991 Aug;38(2):105-13.
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]
HC, Lu RB, Shiah IS, Hwang CC.
Plasma free 3-methoxy-4-hydroxyphenylglycol
predicts response to fluoxetine.
Biol Psychiatry. 1997 Apr
"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.
serotonin and plasma tryptophan in depressed patients: effect of drug treatment
and clinical outcome.
Neuropsychopharmacology. 1994 May;10(3):207-14.
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]
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.
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]
Platelet serotonin and plasma tryptophan decreases in endogenous
depression. Clinical, therapeutic, and biological correlations.
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
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.
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]