[See also Serotonergic
Genes and Unipolar Depression / SSRI Response or 5-HT1B
and Aggression/ Impulsivity] [Note that serotonin transporter research is
not included on this page.]
Gibbons RD, Davis
Consistent evidence for a biological subtype of depression characterized
by low CSF monoamine levels.
Acta Psychiatr Scand 1986 Jul;74(1):8-12
of previously published CSF monoamine data has revealed statistical evidence for
a biological subtype of depression, characterized by abnormally low CSF-5HIAA
and CSF HVA. Using maximum likelihood gaussian mixture analysis we were able to
resolve the empirical frequency distributions of both CSF HVA and CSF 5-HIAA into
two component normal mixtures. Simultaneous analysis of both CSF 5-HIAA and CSF
HVA revealed a two component bivariate normal mixture distribution in which 35%
of the depressed patient sample were classified in the low subgroup. No evidence
for mixture distributions was found in controls. Analysis of CSF MHPG revealed
a single component normal distribution with virtually identical mean and variance
in both patients and controls. These results are shown to be virtually identical
to parallel analyses conducted on CSF monoamine data collected as part of the
NIMH collaborative study on the psychobiology of depression study." [Abstract]
M, Thoren P, Traskman L, Bertilsson L, Ringberger V.
depression"--a biochemical subgroup within the affective disorders?
1976 Feb 6;191(4226):478-80
"The distribution of 5-hydroxyindoleacetic
acid (5-HIAA) concentrations in the cerebrospinal fluid of 68 depressed patients
was bimodal. Twenty-nine percent of the patients were in the lower mode, with
a concentration of 5-HIAA below 15 nanograms per milliliter. Although there were
no differences in overall severity of depression between the two modes, there
was a significant correlation between the concnetration of 5-HIAA and severity
of depression in the lower, but not in the upper, mode. The finding suggests the
existence of a biochemical subgroup of depressive disorder, characterized by a
disturbance of serotonin turnover." [Abstract]
GR, Delgado PL, Charney DS.
The revised monoamine theory of depression:
a modulatory role for monoamines, based on new findings from monoamine depletion
experiments in humans.
Pharmacopsychiatry 1996 Jan;29(1):2-11
"The new hypothesis most consistent with this new data is that the monoamine
systems are only modulating "other" brain neurobiologic systems which
have a more primary role in depression. The modulatory or "antidepressant"
function of the monoamine systems appears to be only necessary during drug induced
recovery and the maintenance of recovery after a prior episode. These clinical
studies point to the need for more fundamental research on the interaction of
monoamine systems with other brain neurobiologic mechanisms relevant to depression."
Graciela, Blier, Pierre
Autoregulation of Serotonin Neurons: Role
in Antidepressant Drug Action
Pharmacol Rev 1999 51: 533-591
CSF 5-HIAA correlates
with neuroticism in depressed patients.
J Affect Disord
"BACKGROUND: To examine for relationships between
neurotransmitters and personality. METHOD: 27 depressed patients had cerebrospinal
fluid (CSF) monoamine metabolites measured and completed the Eysenck Personality
Questionnaire (EPQ). RESULT: CSF concentrations of the serotonin metabolite 5-hydroxyindoleacetic
acid (5-HIAA) correlated significantly with EPQ neuroticism scores. CONCLUSION:
Central serotonin may play a role in neuroticism, a personality dimension predisposing
to depression. LIMITATION: The positive correlation may partly reflect collinear
relationships between both variables and anxiety/depression." [Abstract]
Relationships between clinical symptoms and monoamine metabolite
concentrations in biochemically defined subgroups of depressed patients.
Psychiatr Scand 1988 Dec;78(6):720-9
"In 28 patients with primary depression,
relationships were sought between rating scores on the Montgomery-Asberg Depression
Rating Scale and the concentrations of the monoamine metabolites 5-hydroxyindoleacetic
acid (5-HIAA), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylglycol (HMPG)
in cerebrospinal fluid (CSF). Among the single items in the rating scale, reported
sadness correlated negatively with HMPG. No other significant relationships were
found in the total group of patients. However, in subgroups with low or high concentrations
of monoamine metabolites, several significant relationships were found, such as
a negative correlation between inner tension and concentration difficulties, respectively,
and 5-HIAA in the low-HMPG subgroup. Curvilinear relationships were found between
pessimistic thoughts and 5-HIAA in the high-5-HIAA subgroup and between apparent
sadness and 5-HIAA in the low-HMPG subgroup. Suicidal thoughts tended to correlate
in a curvilinear way with the ratio of HMPG/5-HIAA in the low-HVA and the high-HMPG
subgroups, but the curves were mirrored. The results indicate that relationships
between clinical symptoms and monoamine metabolite homeostasis in CSF are qualitatively
and quantitatively different in defined high-and low-monoamine subgroups of depressed
SC, Crompton MR, Czudek C, Horton RW, Katona CL, Reynolds GP.
concentrations and turnover in brains of depressed suicides.
Res 1989 Nov 20;502(2):332-40
"5-Hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic
acid (5-HIAA) concentrations and 5-HT turnover (5-HIAA/5-HT) were determined in
6 brain regions from 19 suicide victims in whom a retrospective diagnosis of depression
was established, and 19 age- and sex-matched control subjects. Thirteen of the
suicides were free of psychoactive drugs at the time of death; 5 were receiving
antidepressant drugs. 5-HT, 5-HIAA and 5-HT turnover did not differ significantly
between the total, drug-free and antidepressant-treated suicides and controls
in frontal and temporal cortex, caudate and hippocampus. 5-HIAA concentration
was significantly higher in amygdala of drug-free suicides than controls, whereas
5-HT and 5-HT turnover did not differ. 5-HT concentration was significantly lower
in putamen of the total and antidepressant-treated suicides and a similar reduction
was also apparent in the drug-free suicides. 5-HT turnover in putamen was significantly
higher in the total and drug-free suicides compared to controls. 5-HT and 5-HIAA
concentrations in putamen were significantly lower in drug-free suicides who died
by non-violent means than in those who died by violent means. Differences between
controls and suicides could not be attributed to age, sex or postmortem delay.
These results offer no support for the view that 5-HT turnover is reduced in depressed
subjects who commit suicide." [Abstract]
Owen F, Chambers DR, Cooper SJ, Crow TJ, Johnson
JA, Lofthouse R, Poulter M.
Serotonergic mechanisms in brains of
Brain Res 1986 Jan 1;362(1):185-8
mechanisms have been investigated in postmortem brain samples from controls and
suicide victims. The concentrations of 5-hydroxytryptamine (serotonin; 5-HT) and
5-hydroxyindoleacetic acid (5-HIAA) were determined in occipital cortex and hippocampus
and the high-affinity binding of ligands to the 5-HT1, 5-HT2 and imipramine-binding
sites was assessed in frontal cortex, occipital cortex and hippocampus. The only
significant difference between the two groups was a modest increase in 5-HIAA
levels in the hippocampus of suicide victims. There was no evidence to suggest
that those suicide victims with a clinical history of depression represented a
subgroup with altered metabolite levels or binding values. The storage conditions
of the samples were not related to the metabolite levels or binding values. There
was, however, a significant positive correlation between [3H]imipramine binding
and age in some brain regions. The results do not provide any evidence of gross
alterations in 5-HT mechanisms in suicide or depression." [Abstract]
Roy A, Pickar D, Linnoila M, Doran AR, Paul SM.
fluid monoamine and monoamine metabolite levels and the dexamethasone suppression
test in depression. Relationship to life events.
Psychiatry 1986 Apr;43(4):356-60
"The cerebrospinal fluid levels of norepinephrine
and six monoamine metabolites were measured in 23 patients meeting DSM-III criteria
for major depressive episode, 15 of whom also met criteria for melancholia. Life
events during the six-month period before the onset of depression were recorded
using Paykel's method. There was no difference in Hamilton depression ratings
between patients with life events and those without. However, depressed patients
who did not have a life event in the six months before the onset of depression
had significantly lower levels of the dopamine metabolite homovanillic acid and
the serotonin metabolite 5-hydroxyindoleacetic acid than those with life events.
The incidence of nonsuppression on the dexamethasone suppression test was also
greater in patients with a major depressive episode who did not have an undesirable
life event than in those who did. Thus, the presence or absence of life events
led to a separation into biologically distinct groups." [Abstract]
A, Nimeus A.
The dexamethasone suppression test and CSF-5-HIAA in
relation to suicidality and depression in suicide attempters.
Psychiatry. 2003 Jun;18(4):166-71.
"This study tested suicidality in relation
to cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and the dexamethasone
suppression test. Patients with nonsuppression of cortisol had the highest scores
of the Suicide Assessment Scale (SUAS) and the Montgomery Asberg Depression Rating
Scale (MADRS), respectively (P < 0.05; P < 0.01). The results persisted
when analysed for covariance with CSF-5-HIAA. We have previously noted an elevated
suicide risk in suicide attempters with high SUAS-scores, why a large part of
nonsuppressors may be at high risk for future suicide." [Abstract]
Geracioti TD Jr, Loosen PT, Ekhator NN, Schmidt
D, Chambliss B, Baker DG, Kasckow JW, Richtand NM, Keck PE Jr, Ebert MH.
of serotonergic and noradrenergic systems in depression: preliminary evidence
from continuous cerebrospinal fluid sampling.
"We used the technique of continuous cerebrospinal fluid
(CSF) sampling to test the following hypotheses regarding CNS monoaminergic systems
in depression: (1) absolute concentrations of the informational substances tryptophan
and 5-hydroxyindoleacetic acid (5-HIAA) are altered in the CNS of depressed patients
(2) abnormal rhythms of tryptophan and/or 5-HIAA, or defective conversion of tryptophan
to serotonin (5HT), exist in the CNS of depressed patients, and (3) the relationship
between the CNS 5HT and norepinephrine (NE) systems is disrupted in depressed
patients. We obtained 6-h concentration time series of tryptophan, 5-HIAA, NE,
and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF of 10 patients with major
depression and in 10 normal volunteers. No significant differences in CSF tryptophan,
5-HIAA, NE, or MHPG concentrations or rhythms were observed between normal volunteers
and depressed patients. Neither were there differences in the mean tryptophan-to-serotonin
ratio. However, a negative linear relationship was observed between mean concentrations
of 5-HIAA and NE in the CSF of the normal volunteers (r = 0.916 [r2 = 0.839],
df = 9, P < 0.001) while, in contrast, depressed patients showed no such relationship
(r = +0.094 [r2 = 0.00877], df = 9, n.s.). Furthermore, the correlation coefficients
expressing the relationship between CSF MHPG and CSF 5-HIAA within the normal
and depressed groups were significantly different. These data support the hypothesis
that a disturbance in the interaction between the serotonergic and noradrenergic
systems can exist in depressive illness in the absence of any simple 5HT or NE
deficit or surplus." [Abstract]
A, Pickar D, Linnoila M, Doran AR, Ninan P, Paul SM.
fluid monoamine and monoamine metabolite concentrations in melancholia.
Res 1985 Aug;15(4):281-92
"Cerebrospinal fluid levels of norepinephrine
and six monoamine metabolites were measured in 28 medication-free depressed patients.
Patients with a major depressive episode with melancholia (n = 15) had significantly
lower levels of the three dopamine metabolites: homovanillic acid (HVA), dihydroxyphenylacetic
acid (DOPAC), and conjugated dihydroxyphenylacetic (CONJDOPAC), when compared
with a combined group of patients with a major depressive episode or dysthymic
disorder (n = 13). In patients with major depressive episode with melancholia,
levels of HVA and of the serotonin metabolite 5-hydroxyindoleacetic acid significantly
correlated with the severity of depression. In the total group of 28 depressed
patients, cerebrospinal fluid (CSF) levels of norepinephrine significantly correlated
with symptoms of anxiety. In both patients with major depressive episode and major
depressive episode with melancholia, those who were non-suppressors on the dexamethasone
suppression test had significantly higher CSF levels of the norepinephrine metabolite
3-methoxy-4-hydroxyphenylglycol compared to those who were suppressors."
SH, Maas JW, Bowden CL, Davis JM, Hanin I, Javaid J.
CSF and urinary
biogenic amines and metabolites in depression and mania. A controlled, univariate
Arch Gen Psychiatry 1983 Sep;40(9):999-1010
of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol
(MHPG) in the CSF, and norepinephrine (NE), epinephrine (E), vanillylmandelic
acid, normetanephrine, metanephrine, and MHPG in the urine, were measured in 151
hospitalized patients with affective disorders and in 80 healthy controls following
a two-week drug-free period. Unipolar and bipolar depressed subjects differed
only in NE and E levels. Compared with controls, depressed subjects had higher
CSF MHPG levels, women had higher 5-HIAA levels, and men had lower HVA levels.
All urinary metabolites were elevated in depression and mania, with the exception
of MHPG. The patterns of NE-E differences discriminated among the forms of affective
disorders. These data suggest an imbalance of monoamine transmission in depression,
characterized by the hyperactive sympathetic nervous system and adrenal medulla.
However, MHPG may not be the measure of choice to reflect this imbalance, necessitating
measurement of total body monoamine output." [Abstract]
A, Sorensen AS, Rafaelsen OJ, Werdelin L, Alling C, Linnoila M.
and 5-HIAA in cerebrospinal fluid in depression.
Disord 1987 Jan-Feb;12(1):13-22
"CSF 5-HT and 5-HIAA were measured in
endogenously depressed patients (ICD-9) (n = 23) and controls (n = 11). Distribution
of sex, age and body height was similar in the two groups. Non-parametric statistics
were used. In depressed patients CSF 5-HT concentrations were found to be higher
(P less than or equal to 0.01) than in controls. A further classification of the
depressed patients by the Newcastle Scale showed that the highest values were
found in the endogenous group compared to the non-endogenous group (P less than
or equal to 0.02). CSF 5-HIAA was found to be equal in the two groups, even when
pairs matched for height were compared. No relation between clinical recovery
due to drug treatment and changes in CSF 5-HT was seen." [Abstract]
E, Markianos M, Malliaras D, Stefanis C.
in delusional depression.
Am J Psychiatry 1988 Feb;145(2):214-7
authors assayed plasma dopamine beta-hydroxylase activity, platelet monoamine
oxidase (MAO) activity, plasma prolactin, the urinary monoamine metabolites 3-methoxy-4-hydroxyphenylglycol
(MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), and
urinary cAMP from 18 delusional and 22 nondelusional depressed inpatients. No
significant differences between the two groups were found." [Abstract]
A, Werdelin L, Gjerris F, Sorensen PS, Rafaelsen OJ, Alling C.
metabolites in depression, dementia and in controls.
Psychiatr Scand 1987 Jun;75(6):619-28
"Lumbar CSF concentration of 5-HIAA,
MHPG, and HVA were measured in patients with depression, dementia due to normal
pressure hydrocephalus (NPH) and in controls. Moreover, ventricular concentrations
of the metabolites were measured in patients with NPH. It was aimed to match patients
and controls for age, sex, and body height. Non-parametric statistics were used
throughout the study. No differences in lumbar concentrations of CSF 5-HIAA, MHPG
and HVA were found between the different diagnostic groups." [Abstract]
Reddy PL, Khanna S, Subhash MN, Channabasavanna SM,
CSF amine metabolites in depression.
Psychiatry 1992 Jan 15;31(2):112-8
"The amine metabolites, namely homovanillic
acid (HVA) and 5-hydroxy indoleacetic acid (5-HIAA) were measured in cerebrospinal
fluid (CSF) of depressives (n = 30) and controls (n = 30). Depressed patients
had significantly lower HVA levels than controls. No significant differences were
noted between the two groups in 5-HIAA levels. However, the differences between
the groups for the CSF HVA/5-HIAA ratio were larger than those for the CSF HVA
alone (p less than 0.01 versus p less than 0.025, respectively). HVA levels correlated
positively with monoamine oxidase activity and adenosine deaminase activity."
CA, Faull KF, King RJ, Whiteford HA, Barchas JD, Berger PA.
metabolites and depression.
Psychiatry Res 1987 May;21(1):1-7
fluid (CSF) amine metabolites were measured in 37 male subjects with major depressive
disorder. Scores on the Hamilton Rating Scale for Depression (HRSD) correlated
significantly with 5-hydroxyindoleacetic acid (5HIAA) and with homovanillic acid
(HVA). In addition, the single suicide item of the HRSD correlated significantly
with 5HIAA. Further, 5HIAA and HVA correlated significantly with each other. There
was a significant positive correlation between HVA and two HRSD items, the depersonalization/derealization
item and the paranoid item. Since lumbar CSF metabolite concentrations may reflect
central nervous system activity of parent amines, these data suggest a relationship
between depression and decreased dopaminergic and serotonergic activity."
DE Jr, Katz MM, Maas JW, Swann A, Casper R, Davis JM.
fluid amine metabolites. Relationships with behavioral measurements in depressed,
manic, and healthy control subjects.
Arch Gen Psychiatry
"We studied 99 hospitalized depressed, 14 manic,
and 61 healthy control subjects and evaluated relationships during a drug-free
baseline period between behavioral measures (postulated to be associated with
brain norepinephrine, dopamine, and serotonin function) and metabolites of these
neurotransmitters sampled from lumbar cerebrospinal fluid (CSF): 3-methoxy-4-hydroxyphenylglycol
(MHPG), homovanillic acid, and 5-hydroxyindoleacetic acid. Depressed subjects
with increased anxiety, agitation, somatization, and sleep disturbance were found
to have significantly elevated concentrations of CSF MHPG; this relationship was
not found in the healthy controls. A correlation between CSF MHPG level and an
anxiety/agitation dimension measured in all subjects was statistically significant
but explained a modest portion of the total variance. No consistent relationships
were found between CSF MHPG and depression/retardation, hostility/interpersonal
sensitivity, and global severity, nor did any of these measures correlate significantly
with the levels of the other monoamine metabolites, although some trends were
found. Other factors did not account for the relationships between CSF MHPG and
some behavioral measures, including diagnostic subgroup, motor movement, age,
sex, and premenopausal or postmenopausal status in women. Suggested relationships
among drug treatment modality, eventual treatment outcome, behavioral and mood
state at baseline, and these metabolite levels will require further analyses."
WO, Faull KF, Whiteford HA, Borchert C, Csernansky JG.
serum cortisol, and age differentially predict vegetative and cognitive symptoms
Biol Psychiatry 1990 Feb 1;27(3):311-8
studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic
acid (5-HIAA) and serum cortisol levels are related to overall symptom severity
in depression. In the present study, 30 unmedicated inpatients meeting Research
Diagnostic Criteria (RDC) criteria for depression participated in serum cortisol
collection and a lumbar puncture for CSF. A multiple regression evaluated the
ability of CSF 5-HIAA, serum cortisol, and age to predict cognitive and vegetative
symptom clusters of the Hamilton Rating Scale for Depression. The multiple regression
to predict the vegetative symptom cluster was highly significant overall (p =
0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms.
The regression to predict the cognitive cluster narrowly missed overall significance
(p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and
5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not
predict cognitive symptoms. The results suggest a dissociation between serum cortisol
levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters
in depression." [Abstract]
GM, Stancer HC, Warsh JJ, Persad E.
and endocrine responses in depression.
Biol Psychiatry 1985;9(5-6):613-7
(MHPG), 3-4-dihydroxyphenylethyleneglycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA),
plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH)
were measured before and after the injection of thyrotropin releasing hormone
(TRH) in healthy subjects and depressed patients with primary affective disorder.
The TSH response to TRH did not differ in depressed compared with control subjects.
A trend (.05 less than p less than .10) toward a lower PRL response appeared in
male depressed compared with male control subjects. GH levels did not consistently
change after TRH. In all subjects the TSH response correlated positively with
pre- and post-TRH urinary MHPG. The PRL response correlated negatively with pre-TRH
urinary 5-HIAA. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed
SK, Cross CK, Koslow S, Katz MM, Kocsis J, Maas JW, Landis H.
and suicidal behavior in depressed patients.
"The present study was undertaken in order to
further explore the relationship between monoamine levels and hypothalamic-pituitary-adrenocortical
(HYPAC) functioning and suicidal behavior in depressed patients. One hundred and
thirty-two depressed inpatients participated in the NIMH Collaborative Study on
the Psychobiology of Depression. Similar to previous reports, our suicide attempters
were younger, more likely to be bipolar, had an earlier age at onset, and displayed
more psychotic features. No correlation between cortisol hypersecretion or Dexamethasone
Suppression Test (DST) nonsuppression and suicide attempts were found. Only the
pre-DST evening plasma cortisol distinguished the groups, being lower in the attempter
group. We were unable to confirm the previously reported correlation between cerebrospinal
fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and suicide attempts. Of the monoamines
examined, only urinary and plasma 3-methoxy-4-hydroxphenylglycol (MHPG) differed
between suicide attempters and nonattempters, showing lower levels in the attempter
group. There was a trend for CSF MHPG in the same direction. This latter reduction
was restricted to the bipolar group." [Abstract]
Lambert G, Johansson M, Agren H, Friberg P.
brain norepinephrine and dopamine release in treatment-refractory depressive illness:
evidence in support of the catecholamine hypothesis of mood disorders.
Gen Psychiatry 2000 Aug;57(8):787-93
"BACKGROUND: The etiology of depressive
illness has been linked with brain monoaminergic neuronal dysfunction, yet the
development of sensitive markers of endogenous depression has proven difficult.
METHODS: Using catheters placed in an internal jugular vein, we estimated the
release of brain monoamine neurotransmitters in 19 healthy volunteers and in 9
patients with nonbipolar depressive illness refractory to medication at rest and
following intravenous desipramine hydrochloride. Venoarterial plasma concentration
gradients were used to quantify the amount of neurotransmitters stemming from
the brain. Cerebral oxidative metabolism was assessed concurrently from measurements
of oxygen and carbon dioxide gas exchange via the process of regional indirect
calorimetry. RESULTS: The brains of these patients exhibited reduced venoarterial
norepinephrine (4.0 +/- 2.7 nmol/L vs 0.7 +/- 1.3 nmol/L) and homovanillic acid
concentration gradients (8.3 +/- 7.8 nmol/L vs 3.1 +/- 1.9 nmol/L), and used an
energy source other than glucose. Internal jugular 5-hydroxyindoleacetic acid
concentration gradients were not reduced in the patients with depressive illness.
While both the reduction in norepinephrine turnover and the defect in cerebral
metabolism were normalized following pharmacological blockade of the norepinephrine
transporter with desipramine, paradoxically it was the brain's turnover of dopamine
that bore a significant relation to the patients' clinical status (r(s) = 0.79,
P =.02). The positive nature of this relationship remains difficult to reconcile.
CONCLUSIONS: In accordance with the monoamine hypothesis, a deficit in brain norepinephrine
and dopamine exists in patients with depressive illness. Moreover, the brains
of these patients use an energy source other than glucose, a situation that is
normalized following the acute pharmacological blockade of the norepinephrine
transporter with the tricyclic antidepressant, desipramine." [Abstract]
M, Garnier JP, Tremine T, Bousquet B, Manet L, Dreux C, Lauzel JP.
of 3-methoxy-4-hydroxyphenyethylene-glycol and its urinary conjugates. Value in
the diagnosis and therapeutic follow-up of depression]
Biol (Paris) 1988 Mar;36(3):217-23
"In psychiatric illness like depression,
difference is essential between noradrenergic and serotoninergic sources. Therefore
the measurement of urinary excretion of MHPG (3-methoxy-4-hydroxy-phenylethylene-glycol)
is interesting, because MHPG seems to be the best reflect of central noradrenergic
activity. Analytical assay of MHPG includes an enzymatic hydrolysis and an extraction
by ethyl acetate. Separation is conducted by HPLC with fluorometric detection
for MHPG and VMA, and electrochemical detection for 5-HIAA, which measurement
is simultaneous. Quality control is evaluated (detection limit, linearity, precision,
reproducibility, hydrolysis and extraction efficiency). Control values of 15 healthy
subjects are 18.9 +/- 8.0 mumol/24 h of total MHPG, 1.5 +/- 1.0 of free MHPG,
8.5 +/- 2.0 of sulfate, and 10.7 +/- 4.4 of glucuronide MHPG (m +/- 2 sigma).
In our study on depression, the best biological witness seems to be the sulfate-MHPG:
in 16 depressed patients without treatment, its rate is very lowered (1.2 +/-
1.2 mumol/24 h). Total and glucuronide MHPG decrease weaker than sulfate (respectively
-51% and -65%), while free MHPG increases (+ 193%) versus controls. Urinary VMA
and 5-HIAA, peripheric catabolites of respectively adrenalin and serotonin are
not significantly altered. There is no correlation neither between urinary sulfate-MHPG
and scale evaluation before treatment, nor between urinary sulfate-MHPG and clinic
improvement after antidepressive treatment." [Abstract]
B, Baghai TC, Minov C, Schule C, Schwarz MJ, Zwanzger P, Rupprecht R, Moller HJ.
P serum levels are increased in major depression: preliminary results.
Psychiatry. 2003 Mar 15;53(6):538-42.
"BACKGROUND: Substance P (SP) is
thought to have an impact in the pathophysiology of depression and the mechanism
of action of antidepressant drugs. The aim of this study was to analyze the serum
SP levels in healthy control subjects and in depressed patients before and after
antidepressant treatments. METHODS: Twenty-three patients with major depression
and 33 control subjects participated in the study. Using an enzyme immunoassay,
the SP serum levels were determined in patients at baseline (before treatment)
and after 2 and 4 weeks of antidepressant therapy. Determinations of SP in control
subjects were carried out twice, at baseline and after 4 weeks. RESULTS: The mean
baseline SP serum concentration was significantly higher in depressed patients
as compared with control subjects (p <.001). Repeated measurements in control
subjects showed that SP remains relatively constant over a period of 4 weeks.
Although in depressed patients there was no overall change in the mean SP levels
between baseline and 4 weeks' treatment, 37% of them exhibited a decrease of SP
(15%-50%), which can be correlated to a better drug response than an increase
in SP concentration after treatment (p =.001). CONCLUSIONS: Our data show that
serum SP levels are increased in a proportion of patients with major depression
and might thus indicate a subgroup of the disorder in which neuropeptides have
a key position. Future studies are needed to clarify whether the observed SP decrease
in treatment responders can be attributed to a specific class of drugs."
Brown GL, Linnoila MI.
metabolite (5-HIAA) studies in depression, impulsivity, and violence.
J Clin Psychiatry 1990 Apr;51 Suppl:31-41; discussion 42-3
central nervous system (CNS) mechanism for the expression of emotions and behaviors
in animals has now been proposed for over 50 years. More specifically, alterations
in CNS serotonin associated with aggressive behavior in certain animal models
have been among the most frequent, reliable, and replicable findings. Because
alterations in CNS monoamines, i.e., catechols and indols, have been related to
hypotheses for affective disorders and associated with both suicidal and aggressive
behaviors, human clinical implications have emerged. The original studies, which
reported an association between low cerebrospinal fluid 5-hydroxyindole-acetic
acid concentration and impulsive, destructive behaviors, particularly where aggression
and violence are involved, have now been replicated rather consistently in a number
of countries and cultures." [Abstract]
GP, Oquendo MA, Malone KM, Huang YY, Ellis SP, Mann JJ.
suicide attempts, and depression: relationship to cerebrospinal fluid monoamine
Biol Psychiatry 2001 Nov 15;50(10):783-91
We have proposed a stress-diathesis model for suicidal behavior, in which major
depression is a stressor and the diathesis is shared with aggression. Neurotransmitter
correlates of the stress or diathesis have not been adequately evaluated by previous
studies, because they did not simultaneously examine the relationship of multiple
neurotransmitters to all three psychopathologies in the same population. In the
present study we investigated the relationship of monoamine metabolites to aggressivity,
suicidal behavior, and depression in patients with mood disorders. METHODS: Ninety-three
drug-free subjects with a major depressive episode underwent lumbar puncture and
psychiatric evaluation. Cerebrospinal fluid CSF levels of 5hydroxyindolacetic
acid (5-HIAA), homovanillic acid (HVA) and methoxy-hydroxy-phenylglycol (MHPG)
were assayed. The relationships between monoamine metabolites and clinical variables
were statistically evaluated. RESULTS: Higher lifetime aggressivity correlated
significantly with lower CSF 5-HIAA. Lower CSF 5-HIAA and greater suicidal intent
were found in high-lethality suicide attempters compared with low-lethality suicide
attempters. Low-lethality attempters did not differ biologically from nonattempters.
No correlation between CSF HVA and any of the psychopathological variables was
found. Only aggression showed a trend statistically in correlating positively
with CSF MHPG levels. CONCLUSIONS: Lower CSF 5-HIAA concentration was independently
associated with severity of lifetime aggressivity and a history of a higher lethality
suicide attempt and may be part of the diathesis for these behaviors. The dopamine
and norepinephrine systems do not appear to be as significantly involved in suicidal
acts, aggression, or depression. The biological correlates of suicide intent warrant
further study." [Abstract]
D, Jamain S, Kollenbach K, Alvarez JC, Lecrubier Y, Gilton A, Jullien P, Lesieur
P, Bonnet F, Spreux-Varoquaux O.
CSF 5-HIAA levels are lower in impulsive
as compared to nonimpulsive violent suicide attempters and control subjects.
Psychiatry 1999 Jun 15;45(12):1572-9
"BACKGROUND: We studied CSF 5-HIAA
and HVA concentrations in violent suicide attempters and examined their relationship
with depression, anxiety, and impulsivity. METHODS: CSF 5-HIAA and HVA concentrations
were determined very shortly after hospital admission and compared to those of
a matched control population. Clinical evaluation was performed concomitantly;
the level impulsivity was evaluated by the Impulsivity Rating Scale (IRS). RESULTS:
Twenty-three patients and 23 control subjects were included. According to the
IRS, 14 patients were classified as impulsive, including all patients suffering
from personality disorders, and 9 as nonimpulsive, with a main DSM-IIIR diagnosis
of melancholia. CSF 5-HIAA concentrations in the suicide group were significantly
lower than in control subjects. This difference was entirely due to the impulsive
suicide attempters. There was an inverse correlation between the IRS score and
CSF 5-HIAA (r = -.47, p = .02) and only a trend for HVA (r = -.41, p = .078) levels
in the suicide group. CONCLUSIONS: This study of a group of violent suicide attempters
distinguished a subgroup of patients diagnosed with personality disorder with
high impulsivity scores and a subgroup of patients with the main diagnosis of
severe depression. CSF 5-HIAA was significantly lower in impulsive violent attempters
than in nonimpulsive violent attempters, therefore desintangling violence from
impulsivity and linking this biologic abnormality to impulsivity." [Abstract]
M, Traskman L, Thoren P.
5-HIAA in the cerebrospinal fluid. A biochemical
Arch Gen Psychiatry 1976 Oct;33(10):1193-7
incidence of suicidal acts was studied in 68 depressed patients and related to
the level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid. The
distribution of 5-HIAA levels was bimodal. Patients in the low 5-HIAA mode (below
15 ng/ml) attempted suicide significantly more often than those in the high mode,
and they used more violent means. Two of the 20 patients in the low mode, and
none of the 48 patients in the high mode died from suicide." [Abstract]
Spreux-Varoquaux O, Alvarez JC, Berlin I, Batista
G, Despierre PG, Gilton A, Cremniter D.
in plasma 5-HIAA and platelet serotonin concentrations in violent suicide attempters:
relationships with impulsivity and depression.
2001 Jun 29;69(6):647-57
"Brain serotonergic systems may participate in
the regulation of mood, impulsivity and aggressive behavior. Because some monoaminergic
mechanisms seem to be similar in the central nervous system and peripheral tissues,
we tested whether serotonergic or dopaminergic biochemical parameters in peripheral
venous blood are related or not to violent suicide behavior.We simultaneously
studied plasma serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic
acid (HVA) and platelet 5-HT content in patients within 3 days following a violent
suicide attempt and in matched healthy controls. We examined their relationship
with depression and impulsivity. Twenty seven drug-free suicide attempters and
controls were included. Plasma 5-HIAA and platelet 5-HT concentrations were lower
in suicide attempters than in controls. Fifteen patients were classified as impulsive
(I), including all patients suffering from personality disorder and alcohol abuse,
and 12 as non impulsive (NI), mostly melancholics. MADRS scores were similar in
both I and NI suicide attempters.When controlling for age, plasma 5-HIAA was lower
in I than in NI suicide attempters or controls; these findings are similar to
those we observed recently with CSF 5-HIAA in I and NI violent suicide attempters.
Contrarily, platelet 5-HT levels were lower in NI than in I patients or controls.
Plasma HVA was not associated with suicide behavior. Plasma 5-HIAA concentration
was inversely associated with the degree of impulsivity and platelet 5-HT with
the intensity of depression. This study indicates that each peripheral serotonergic
index is specifically related to a distinct clinical feature and shows differential
alteration according to the impulsivity group. In I and NI drug-free violent suicide
attempters an inverse figure between plasma 5-HIAA and platelet 5-HT data was
observed indicating a non parallelism between these two peripheral variables.
Further prospective studies are needed to investigate whether these peripheral
serotonergic parameters may be used as helpful early predictors of violent suicide
JJ, Malone KM.
Cerebrospinal fluid amines and higher-lethality suicide
attempts in depressed inpatients.
Biol Psychiatry 1997 Jan
"Previous studies have found that not all suicide attempters
with major depression have reduced serotonergic activity based on low cerebrospinal
fluid 5-hydroxyindoleacetic acid (CSF- 5-HIAA) levels. In this study we hypothesized
that serotonergic function is lower in depressed patients who have carried out
high-lethality suicide attempts resulting in more medical damage, which might
explain differences in serotonergic activity among depressed suicide attempters.
We assessed the relationship of CSF 5-HIAA and other amine metabolites to the
most lethal lifetime suicide attempt in 22 drug-free inpatients with major depression.
CSF 5-HIAA levels were lower in depressed patients with a history of a high-lethality
or well-planned suicide attempt compared to depressed patients with a history
of only low-lethality suicide attempt(s). Other CSF monoamine metabolites did
not correlate with suicidal behavior. Low serotonergic activity may correlate
with a predisposition to more lethal suicide attempts in major depression."
CM, Arato M, Kilts CD.
Aminergic studies and cerebrospinal fluid
cations in suicide.
Ann N Y Acad Sci 1986;487:221-30
fluid 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) measurements
have been collected over six years from 275 drug-free, recently hospitalized psychiatric
patients, almost exclusively females. In accord with other observations from various
countries, patients who had attempted suicide shortly before admission had significantly
lower mean CSF 5-HIAA concentration and this was particularly true for those using
violent methods. This finding could be replicated in five subsequent samples of
patients evaluated separately and using different assay procedures, and proved
to be independent of the clinical diagnoses. CSF HVA also showed similar tendencies
but it had much larger variance with respect to suicide attempts and therefore
fell short of statistical significance. In two patient populations CSF calcium
and magnesium measurements have been obtained. CSF calcium did not prove to be
related to either suicidal behavior or the diagnosis of major depression; on the
other hand, CSF magnesium was found to be significantly lower in the suicide attempters
and also correlated with CSF 5-HIAA. Nonsuicidal depressives had comparable CSF
calcium and magnesium levels to the controls." [Abstract]
CM, Arato M.
Amine metabolites, neuroendocrine findings, and personality
dimensions as correlates of suicidal behavior.
Res 1983 Dec;10(4):253-61
"Levels of 5-hydroxyindoleacetic acid (5-HIAA)
and homovanillic acid (HVA) were measured in the cerebrospinal fluid (CSF) of
62 female inpatients with major depression (n = 19), schizophrenic disorder (n
= 18), alcohol dependence (n = 13), and other disorders (n = 12). Nineteen patients
had attempted suicide immediately before admission, and six had used violent methods.
Fifty-three patients received a dexamethasone suppression test (DST) following
lumbar puncture and all completed the Marke-Nyman Temperament Scale (Hungarian
version) within 10 days. CSF 5-HIAA was significantly lower in patients who had
made violent suicide attempts, but did not differ between suicide attempters who
had taken drug overdoses and nonattempters. CSF HVA showed no significant differences.
Dexamethasone nonsuppression occurred more frequently among attempters, but this
difference did not reach statistical significance. Among the three personality
dimensions of the Marke-Nyman Scale, validity was lower and stability higher in
suicidal patients; both findings were more pronounced in the violent subgroup.
CSF 5-HIAA and Marke-Nyman validity were inversely correlated to each other in
all three subgroups, and violent attempters could be separated from the other
two groups by their simultaneously low CSF 5-HIAA values and Marke-Nyman validity
CM, Arato M, Papp Z, Kurcz M.
Biochemical markers in suicidal patients.
Investigations with cerebrospinal fluid amine metabolites and neuroendocrine tests.
Affect Disord 1984 Jun;6(3-4):341-50
"141 female psychiatric patients,
suffering from major depression, schizophrenia, alcohol dependence or adjustment
disorder, were investigated for their 5-hydroxyindoleacetic acid (5-HIAA), homovanillic
acid (HVA) and cortisol level in the cerebrospinal fluid (CSF). Dexamethasone
suppression tests were also performed in 111 cases, and TRH/TSH tests in 40 subjects.
Fifty-two patients were hospitalized following a recent suicide attempt, 18 of
which were made using a violent method. The other 34 attempters took tranquilizer
or sedative overdoses. CSF 5-HIAA was significantly lower in violent attempters
in all 4 diagnostic categories. CSF HVA was higher in those taking drug overdoses,
but only in depression (and less markedly in schizophrenia). CSF cortisol did
not differ among either diagnostic or suicidal subgroups. Dexamethasone suppression
was more frequently abnormal in suicidal patients than in nonattempters, and this
difference was more important where the overall nonsuppression rate was lower.
Maximal TSH response to TRH showed an inverse correlation with CSF 5-HIAA, and
it was lowest in the nonattempter group. The difference between violent suicide
attempters and nonattempters in their TSH response was significant. Since these
biochemical changes were more or less independent of clinical diagnoses, it seems
relevant to explore further the biological background of human aggression and
suicide as a separate research direction." [Abstract]
JJ Jr, Saiz-Ruiz J, Perez de los Cobos JC.
of suicide and aggressivity in major depressions (with melancholia): 5-hydroxyindoleacetic
acid and cortisol in cerebral spinal fluid, dexamethasone suppression test and
therapeutic response to 5-hydroxytryptophan.
"5-Hydroxyindoleacetic acid (5-HIAA) and cortisol in
cerebrospinal fluid (CSF), response of the dexamethasone suppression test (DST)
and the clinical response to treatment with 5-hydroxytryptophan (5-HTp) plus carbidopa
were studied in a group of 21 depressed inpatients (major depression with melancholia)
in order to correlate biological findings with psychopathologicalones. A positive
correlation was found between strong suicidal thoughts, suicidal attempts and
self-aggressivity and low concentration of 5-HIAA in CSF and a less significant
but still positive correlation with abnormal DST response and with clinical response
to the treatment." [Abstract]
Faustman WO, King RJ, Faull KF, Moses JA Jr, Benson
KL, Zarcone VP, Csernansky JG.
MMPI measures of impulsivity and depression
correlate with CSF 5-HIAA and HVA in depression but not schizophrenia.
J Affect Disord 1991 Aug;22(4):235-9
"Recent studies have linked impulsivity
with CSF concentrations of both 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic
acid (HVA). One work found a negative correlation between the MMPI psychopathic
deviate (Pd) scale and 5-HIAA in personality disordered men (Brown et al., 1982).
We found that the 5-HIAA/Pd correlation extends (P less than 0.05) to unmedicated
depressed patients (n = 21). A trend was found between HVA and Pd in depression.
There was no relationship between either metabolite and the Pd scale in unmedicated
schizophrenics (n = 24). A significant inverse correlation was found between the
MMPI depression scale and CSF HVA but not 5-HIAA in the depressed patients."
S, Verhoeven WM, van Praag HM.
Cerebrospinal fluid 5-hydroxyindolacetic
acid and aggression: a critical reappraisal of the clinical data.
Clin Psychopharmacol 1995 Sep;10(3):147-56
"Over the past 15 years several
clinical studies have been published dealing with the hypothesis that disturbances
in central serotonergic functioning could be related to outward directed aggression
and impulsivity. Close reading of the 22 relevant reports, however, raises doubt
about the unequivocality of the results across diagnostic boundaries and in comparison
with normal controls. Only eight of the studies are methodologically acceptable
and seem to support the hypothesis. Taking all data together, it is concluded
that some relationship exists between decreased serotonin metabolism, as reflected
by lowered cerebrospinal fluid 5-hydroxyindolacetic acid, and certain aspects
of aggressive behavior in a subgroup of young, male, personality-disordered subjects
with seriously deviant behavior." [Abstract]
H, Agren H.
Self-rated aggression and cerebral monoaminergic turnover.
Sex differences in patients with persistent depressive disorder.
Arch Psychiatry Clin Neurosci. 2003 Aug;253(4):185-92.
violence and impulsivity in humans and primates has frequently been related to
abnormal brain monoaminergic turnover. Self-rated aggression is likely to be clinically
relevant,and its psychobiological basis needs investigation. SUBJECTS: Sixty-six
patients (40 women and 26 men) with persistent depressive disorder (PDD) were
compared with 497 control subjects from the general Swedish population. METHODS:
We administered the Aggression Questionnaire - Revised Swedish Version (AQ-RSV)
to patients and control subjects. In patients, CSF 5-hydroxyindoleacetic acid
(5-HIAA) and 3-methoxy-5-hydroxyphenylglycol (MHPG) in CSF were analyzed. Total
Aggression score and Aggression subfactors 'Physical Aggression','Verbal Aggression','Anger',
and 'Hostility'were correlated with CSF concentrations of 5-hydroxyindoleacetic
acid (5-HIAA),and 3-methoxy-5-hydroxyphenylglycol (MHPG). RESULTS: Overall, Hostility
was positively related to CSF MHPG (t=2.27, p=0.015). Split by sex,Hostility was
related with 5-HIAA in males (r=0.62,p=0.003),and with MHPG in females (r=0.38,
p=0.03). Comparing self rated aggression with age- and sex-matched data from the
general Swedish population, the most prominent deviation was increased Hostility
score among PDD patients. Among patients, all aggression factors were nominally
higher in women than in men, with the most pronounced sex difference in Hostility
(t=-1.89, p=0.04). CONCLUSIONS: Results suggest a clinically meaningful sex difference
in a positive relationship between hostility and serotonergic/noradrenergic turnover
in PDD patients." [Abstract]
Affective disorders and aggression disorders: evidence
for a common biological mechanism.
Suicide Life Threat Behav
"Ever since the discovery that the classical
antidepressants--tricyclics and MA oxidase inhibitors--exert an influence on central
5-HT, this neurotransmitter has been studied in depression, particularly in those
forms responsive to this type of treatment. This chapter reviews the evidence
in favor of a relationship between depression and central 5-HT dysfunctions. Most
of the findings have been derived from patients with depression as the principal
diagnosis. Some data have originated from patients suffering from a somatic illness
and from depression as well. Both peripheral and central data are discussed. Although
no single 5-HT-related finding in depression has so far been unequivocally established,
the available evidence, in balance, justifies the tentative conclusion that disturbances
in 5-HT metabolism can occur in depression. Lowered CSF 5-HIAA, the major indicator
of disturbed central 5-HT metabolism in depression, has also been reported in
aggression disorders, both in patients who had committed suicidal acts and in
those with outward-directed aggression. The finding can not be explained by a
concomitant state of depression. Rather than to discard the classical 5-HT-depression
hypothesis, in favor of a 5-HT-aggression hypothesis, the hypothesis is launched
that disturbances in serotonergic regulation can give rise to both mood and aggression
disorders. This would provide a biological explanation for the clinical observation
that those disorders frequently go hand in hand." [Abstract]
G, Alling C, Blennow K, Regnell G, Traskman-Bendz L.
HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites
in 120 suicide attempters and 47 controls.
"Dysfunctions of central monoaminergic systems are
important elements of the leading biological hypotheses of suicide and depression.
The purpose of the present paper was to study the levels and the relationships
between the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine
metabolite homovanillic acid (HVA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol
(MHPG) in the cerebrospinal fluid (CSF) in 120 hospitalised suicide attempters
and 47 controls (healthy volunteers or patients admitted for minor surgery). The
suicide attempters showed significantly lower HVA levels (174+/-82 vs. 216+/-96
nmol/L, P=0.004), HVA/5HIAA ratios (1.6+/-0.5 vs. 2.1+/-0.6, P=0.0001) and HVA/MHPG
ratios (4.2+/-2.1 vs. 4.8+/-1.7, P=0.02) than the controls. The correlations between
the monoamine metabolites were markedly lower in patients than in controls. CSF
5-HIAA showed no significant differences between patients and controls (107+/-40
vs. 108+/-51 nmol/L) or between violent and non-violent attempters (112+/-58 vs.
105+/-33 nmol/L). The monoamine metabolites showed no significant differences
between survivors and patients who subsequently completed suicide, or between
suicide attempters subgrouped by psychiatric diagnoses. The results suggest that
low HVA levels and altered relationships between the monoamine metabolites are
associated with suicidal behaviour." [Abstract]
Roy A, Karoum F, Pollack S.
in indexes of dopamine metabolism among patients with depression who attempt suicide.
Gen Psychiatry 1992 Jun;49(6):447-50
"Cerebrospinal fluid studies have
reported that low concentrations of the dopamine metabolite homovanillic acid
are associated with suicidal behavior in depression. Although only a small proportion
of homovanillic acid in the urine derives from the brain, we decided to examine
24-hour urinary outputs of homovanillic acid in relation to suicidal behavior
in depression. Patients with depression who had attempted suicide had significantly
smaller urinary outputs of homovanillic acid, dihydroxyphenylacetic acid, and
total body output of dopamine (sum dopamine) than did patients with depression
who had not attempted suicide. Patients with depression who reattempted suicide
during 5-year follow-up had significantly smaller urinary outputs of homovanillic
acid and sum dopamine than did patients who did not reattempt suicide, patients
who never attempted suicide, and normal control subjects, and had significantly
smaller outputs of dihydroxyphenylacetic acid than patients who never attempted
suicide or control subjects. These data suggest that urinary outputs of homovanillic
acid may be peripheral correlates of suicidality in depression. These data add
to data on the low levels of homovanillic acid in cerebrospinal fluid in suggesting
that diminished dopaminergic neurotransmission may play a part in suicidal behavior
in depression." [Abstract]
Recent biologic studies on suicide.
Life Threat Behav 1994 Spring;24(1):10-4
"This paper selectively reviews
the author's recent studies on suicidal behavior in depression. Data are reviewed
from a study of depressed patients who had monoamine metabolites measured in both
the cerebrospinal fluid (CSF) and urine. Depressed patients who had attempted
suicide had significantly reduced CSF concentrations of the dopamine metabolite
homovanillic acid (HVA) and significantly lower urinary outputs of HVA than patients
who had not attempted suicide. Similarly, patients who went on to reattempt suicide
over a 5-year follow-up period had both significantly reduced CSF concentrations
of HVA and lower urinary outputs of HVA than patients who did not reattempt. These
data suggest a role for diminished central dopaminergic neurotransmission in suicidal
behavior in depression. Patients who had made a violent suicide attempt also showed
evidence of dysregulation of the hypothalamic-pituitary-adrenal axis." [Abstract]
L, Asberg M, Bertilsson L, Thoren P.
CSF monoamine metabolites of
depressed patients during illness and after recovery.
Psychiatr Scand 1984 Apr;69(4):333-42
"Repeated lumbar punctures in 16
healthy volunteers showed reproducible concentrations of 5-hydroxyindoleacetic
acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF). In seven
depressed patients, studied during two or three illness periods, the metabolite
concentrations were also fairly stable. In 11 patients CSF concentrations of 5-HIAA,
but not of HVA, were higher after recovery than during depression. This increase
of 5-HIAA after recovery was confined to patients whose initial serotonin metabolite
levels were low. The finding constitutes further evidence of a biochemical heterogeneity
within the depressive disorders, and suggests that patients whose CSF 5-HIAA is
low during a depressive episode may have a less stable serotonin system than other
patients with depressive illness." [Abstract]
Life at risk: markers of suicidality
Psychiatr Dev 1983 Spring;1(1):87-103
hundred and ten patients with Research Diagnostic Criteria (RDC) diagnoses of
major depressive disorders were assessed for present or recent suicidal ideation
and behavior and for suicidal acts earlier in life before current depression using
the Schedule for Affective Disorders and Schizophrenia (SADS). Suicidal scores
were correlated uni- and bivariately with levels of CSF monoamine metabolites
(HVA, 5HIAA, MHPG), urinary MHPG, the proportion post-/predexamethasone plasma
cortisol at 1100 h, and platelet MAO activity (all standardized to same sex, age,
height and weight). Results indicate that all 3 monoamine metabolites and their
interactions are involved in various aspects of suicidality, at least in unipolar
patients. MHPG and 5HIAA (both low or both high) were involved in current or recent
suicidal ideation, and low HVA was mainly associated with past potential lethality
of suicidal acts. Current hypercortisolism was found in patients that earlier
in life had tried to commit dangerous suicides. Bipolar patients (depressives
with a history of manic or hypomanic episodes) had earlier in life significantly
more, and more dangerous, suicidal attempts than the unipolars." [Abstract]
MI, Young SN, Bachevalier J, Gauthier S.
Effect of folic acid and
vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrospinal
Ann Neurol 1982 Nov;12(5):479-84
were measured in cerebrospinal fluid (CSF) from control patients, from patients
suffering from folate deficiency, and from patients with vitamin B12 deficiency.
The folate-deficient patients were classified according to whether they exhibited
a neuropsychiatric syndrome, consisting of organic mental changes, polyneuropathy,
and depression, which responded to folate administration. CSF 5-hydroxyindoleacetic
acid was low in the vitamin B12-deficient patients and in those folate-deficient
patients whose symptoms were not related to folate deficiency. CSF 5-hydroxyindoleacetic
acid returned to normal with folate treatment in the patients exhibiting folate-responsive
neuropsychiatric signs. The data indicate a close association between folate-responsive
neuropsychiatric symptoms and changes in 5-hydroxytryptamine metabolism in the
central nervous system." [Abstract]
The use of diet and dietary components in the study of factors
controlling affect in humans: a review.
J Psychiatry Neurosci
"Although one of the first biological treatments
of a major psychiatric disorder was the dietary treatment of pellagra, the use
of diet and dietary components in the study of psychopathology has not aroused
much interest. This article reviews three areas in which the dietary approach
has provided interesting information. The tryptophan depletion strategy uses a
mixture of amino acids devoid of tryptophan to lower brain tryptophan in order
to study the symptoms that can be elicited. One effect of tryptophan depletion
is a lowering of mood, the magnitude of which seems to depend on the baseline
state of the subject. Therefore, recovered depressed patients often undergo an
acute relapse, while normal subjects show more moderate changes of mood. Totally
euthymic subjects show no lowering of mood, but subjects with high normal depression
scale scores or subjects with a family history of depression show a moderate lowering
of mood. These data indicate that low serotonin levels alone cannot cause depression.
However, serotonin does have a direct effect on mood, and low levels of serotonin
contribute to the etiology of depression in some depressed patients. Folic acid
deficiency causes a lowering of brain serotonin in rats, and of cerebrospinal
fluid 5-hydroxyindoleacetic acid in humans. There is a high incidence of folate
deficiency in depression, and there are indications in the literature that some
depressed patients who are folate deficient respond to folate administration.
Folate deficiency is known to lower levels of S-adenosylmethionine, and S-adenosylmethionine
is an antidepressant that raises brain serotonin levels. These data suggest that
low levels of serotonin in some depressed patients may be a secondary consequence
of low levels of S-adenosylmethionine. They also suggest that the dietary intake
and psychopharmacological action of methionine, the precursor of S-adenosylmethionine,
should be studied in patients with depression. Normal meals have definite effects
on mood and performance in humans. The composition of the meal, in terms of protein
and carbohydrate content, can influence these behaviors. Because protein and carbohydrate
meals can influence brain serotonin in rats, these effects in humans have usually
been interpreted in terms of altered serotonin functioning. However, the current
balance of evidence is against the involvement of serotonin in the acute effects
of protein and carbohydrate meals in humans. The underlying mechanisms involved
are unknown, but there are a variety of possibilities." [Abstract]
L, Urbina M.
Serotonin transporter modulation in blood lymphocytes
from patients with major depression.
Cell Mol Neurobiol.
"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]
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]