Laifenfeld, Daphna, Klein, Ehud, Ben-Shachar, Dorit
Norepinephrine alters the expression of genes involved in neuronal
sprouting and differentiation: relevance for major depression and antidepressant
J Neurochem 2002 83: 1054-1064
research into depression has focused on the involvement of long-term intracellular
processes, leading to abnormal neuronal plasticity in brains of depressed patients,
and reversed by antidepressant treatment. Given a suggested decrease in noradrenergic
transmission in depression, and an antidepressant induced increase in norepinephrine
(NE) level, a possible role for NE in mediating alterations in neuronal morphology
and plasticity was examined. Human neuroblastoma SH-SY5Y cells treated with 10-5
m NE presented an elongated granule-rich cell-body and increased number of neurites,
when compared with non-treated cells. Moreover, cell survival was enhanced in
the presence of NE, while proliferation was inhibited. The above effects suggest
a role for NE in cell differentiation. Indeed similar effects on cell survival
and neurite outgrowth were induced in SH-SY5Y cells by retinoic acid (RA), an
established differentiating agent. Finally, NE treatment resulted in a progressive
decrease in the pluripotent marker Oct4 and an increase in the neuronal growth
cone marker, growth-associated-protein 43 (GAP-43). Alongside these effects, NE-treated
cells presented alterations in the expression of 44 genes as observed in a neurobiology
cDNA microarray. Among the altered genes, an increase in the expression level
of two neurite-outgrowth promoting genes, neural cell adhesion molecule L1 and
laminin, was confirmed by RT-PCR. Taken together, the results support a role for
NE in processes of synaptic connectivity, and may point to a role for this neurotransmitter
in mediating the suggested neuronal plasticity in depression and in antidepressant
RM, Stoddard FJ, Gillin JC, Buchsbaum MS, Runkle DC, Black KE, Bunney WE Jr.
Alterations in motor activity, sleep, and biochemistry in a cycling
Arch Gen Psychiatry 1977 Apr;34(4):470-7
"Biochemical and electrophysiological factors were studied longitudinally
in a rapidly cycling manic-depressive patient. Slow changes in mood, motor activity,
sleep, and urinary norepinephrine levels during the course of each depressed and
manic episode are reported, as well as rapid alterations in many variables at
the time of mood switch. Urinary concentrations of norepinephrine and its metabolite,
3-methoxy-4-hydroxyphenyl glycol (MHPG) were significantly lower in depression
than in mania; norepinephrine but not MHPG excretion increased prior to the switch.
We postulate that the slow behavioral and biological changes preceding switches
in this patient are an important manifestation of the cyclic process in manic-depressive
D, Halaris A, Dysken M, DeMet E, Harrow M, Davis J.
of noradrenergic activity in a rapidly cycling bipolar patient.
J Clin Psychiatry 1984 Jul;45(7):306-9
"Plasma levels of the major norepinephrine
(NE) metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were measured in a rapidly
cycling bipolar patient and her first-degree relatives. The mood state dependence
and the reciprocal relationship between noradrenergic and cholinergic activity
were investigated by assessing mood, thought disorder, and plasma MHPG following
the infusion of physostigmine. A correlation was found between plasma MHPG and
mood states, with exceedingly high levels during mania and hypomania. Levels were
significantly decreased by ECT or combined lithium and chlorpromazine administration.
A pathologic diurnal MHPG pattern was detected during periods of abnormal mood
changes. Infusion of physostigmine led to a prompt reduction in MHPG release and
a marked decline in mood-state measurements and the overall level of thought disorder.
Muscarinic receptors exerting negative feedback control over the synthesis and/or
release of NE may have become supersensitive as a consequence of alpha 2-adrenoceptor
PR, Fergusson DM, Woollard G, Abbott RM, Horwood LJ, Upton J.
catecholamines and plasma hormones predict mood state in rapid cycling bipolar
J Affect Disord 1995 Apr 4;33(4):233-43
"Over the course of 1 year, a patient with a rapid cycling bipolar affective
disorder was followed at weekly intervals to examine whether plasma hormones and
urinary catecholamines could predict current or future mood. Higher cortisol levels
were found to predict depressed mood 3 days after blood sampling, higher urinary
dopamine predicted a manic mood 3 days after blood sampling, urinary norepinephrine
was associated with severity of current mood and prolactin was lower with concurrent
depressed mood. In multivariate analyses of mood against cortisol, prolactin and
three urinary catecholamines, > 50% of the variance in mood state in 3 days
was explained by combinations of these biologic measures, especially cortisol
and urinary dopamine, while all five biologic variables contributed to explaining
50% of the variance in current mood state. Based on the interrelationships between
urinary dopamine, norepinephrine and mood, we postulate the existence of an overcompensating
mechanism which is reflected in opposing correlations between urinary dopamine
and norepinephrine with mood, despite the two urinary catecholamines being positively
P, Gelber S, Kin FN, Nair VN, Schwartz G.
Circadian secretion of
cortisol in bipolar disorder.
J Psychiatry Neurosci 2001
"OBJECTIVE: To compare the 24-h cortisol secretion profiles
of normal control subjects and patients with bipolar disorder who were in the
depressive, manic and euthymic phases of the disorder. PARTICIPANTS: Eighteen
patients, 25-62 years of age, in depressed (n = 5), manic (n = 5) or euthymic
(n = 8) phase of bipolar disorder recruited through a psychiatric outpatient clinic,
and 5 control subjects, 24-41 years of age, recruited through advertisement or
word of mouth. OUTCOME MEASURES: Subjects were interviewed and symptom ratings
were obtained using the Hamilton Depression Rating Scale, Beck Depression Inventory
and Young Mania Scale. Blood collection began at 0800 and continued at hourly
intervals for 24 h. Serum cortisol levels were assayed using a validated commercial
radioimmunoassay kit. RESULTS: An analysis of variance of the area under the cortisol
24-h time-concentration curve (AUC) revealed a significant difference between
the control group and patient groups (F = 3.69, p = 0.03). the mean AUCs of the
patients in the depressed (263.4 micrograms/dL) and hypomanic (262.2 micrograms/dL)
phases were beyond the 95% confidence interval for the controls (120.9-253.3 micrograms/dL).
There were no significant group differences in cosinor acrophase and no significant
effects of sex, education, age of illness onset, duration of illness or duration
of mood state at time of testing on the cortisol measures. Pearson correlations
between symptom rating scores and cortisol secretion variables were not significant.
CONCLUSION: The increases in cortisol secretion in patients in both the depressed
and manic phases of bipolar disorder suggest that cortisol level is probably not
a state marker in bipolar disorder." [Abstract]
[I include this to show that cortisol abnormalities may be different
in non rapid cycling bipolar disorder than in rapid cycling bipolar disorder.]
Wehr TA, Muscettola G, Goodwin FK.
3-methoxy-4-hydroxyphenylglycol circadian rhythm. Early timing (phase-advance)
in manic-depressives compared with normal subjects.
Gen Psychiatry 1980 Mar;37(3):257-63
"Twenty-four-hour (circadian) rhythms
in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, motor activity, and
oral temperature were studied in 14 normal subjects and ten manic-depressive patients.
In both groups, a daily rhythm in MHPG excretion was present, with daytime peaks
and nighttime lows. This pattern of urinary MHPG excretion may reflect a rhythm
in central noradrenergic function. The physiological changes in levels of MHPG
excretion associated with the circadian rhythm were at least as great as pathological
changes associated with manic-depressive illness. Compared with controls, the
timing or phase of circadian rhythms in each variable was one to three hours earlier
in the patients, whether depressed or manic. Although the presence of circadian
rhythms complicates the task of designing clinical research procedures, their
early timing in manic-depressives suggests that disturbances in central biological
clocks may be an integral part of the pathophysiology of affective illness and
may be related to disturbances of sleep and neuroendocrine function associated
with depression." [Abstract]
J, Rodriguez-Puertas R, Meana JJ, Garcia-Sevilla JA, Guimon J.
receptor-mediated activation of G-proteins in brains of suicide victims with mood
disorders: selective supersensitivity of alpha(2A)-adrenoceptors.
Mol Psychiatry 2002;7(7):755-67
"Abnormalities in the density of neuroreceptors
that regulate norepinephrine and serotonin release have been repeatedly reported
in brains of suicide victims with mood disorders. Recently, the modulation of
the [(35)S]GTPgammaS binding to G-proteins has been introduced as a suitable measure
of receptor activity in postmortem human brain. The present study sought to evaluate
the function of several G-protein coupled receptors in postmortem brain of suicide
victims with mood disorders. Concentration-response curves of the [(35)S]GTPgammaS
binding stimulation by selective agonists of alpha(2)-adrenoceptors, 5-HT(1A)
serotonin, mu-opioid, GABA(B), and cholinergic muscarinic receptors were performed
in frontal cortical membranes from 28 suicide victims with major depression or
bipolar disorder and 28 subjects who were matched for gender, age and postmortem
delay. The receptor-independent [(35)S]GTPgammaS binding stimulation by mastoparan
and the G-protein density were also examined. The alpha(2A)-adrenoceptor-mediated
stimulation of [(35)S]GTPgammaS binding with the agonist UK14304 displayed a 4.6-fold
greater sensitivity in suicide victims than in controls, without changes in the
maximal stimulation. No significant differences were found in parameters of 5-HT(1A)
serotonin receptor and other receptor-mediated [(35)S]GTPgammaS binding stimulations.
The receptor-independent activation of G-proteins was similar in both groups.
Immunoreactive densities of G(alphai1/2)-, G(alphai3)-, G(alphao)-, and G(alphas)-proteins
did not differ between suicide victims and controls. In conclusion, alpha(2A)-adrenoceptor
sensitivity is increased in the frontal cortex of suicide victims with mood disorders.
This receptor supersensitivity is not related to an increased amount or enhanced
intrinsic activity of G-proteins. The new finding provides functional support
to the involvement of alpha(2)-adrenoceptors in the pathogenesis of mood disorders."
JJ, Orsulak PJ, Schatzberg AF, Gudeman JE, Cole JO, Rohde WA, LaBrie RA.
Toward a biochemical classification of depressive disorders. I. Differences
in urinary excretion of MHPG and other catecholamine metabolites in clinically
defined subtypes of depressions.
Arch Gen Psychiatry 1978
"The urinary excretion of 3-methoxy-4-hydroxyphenylglycol
(MHPG) and other catecholamine metabolites was measured in a series of 63 patients
with various clinically defined subtypes of depressive disorders. MHPG excretion
was significantly lower in patients with bipolar manic-depressive depressions
and schizo-affective depressions than in patients with unipolar nonendogenous
depressions. Patients with schizophrenia-related depressions also excreted reduced
levels of MHPG when compared with patients with unipolar nonendogenous depressions.
Moreover, levels of urinary epinephrine and metanephrine were significantly lower
in patients with schizophrenia-related depressions. These data, coupled with our
recent finding that patients with schizophrenia-related depressions had significantly
higher levels of platelet monoamine oxidase activity than control subjects of
patients with unipolar endogenous depressions, suggest that we can discriminate
three biochemically discrete subgroups of depressive disorders corresponding to
the following clinically defined subtypes: (1) the bipolar manic-depressive depressions
plus the schizo-affective depressions; (2) the unipolar nonendogenous depressions;
and (3) the schizophrenia-related depressions." [Abstract]
JJ, Orsulak PJ, LaBrie RA, Schatzberg AF, Gudeman JE, Cole JO, Rohde WA.
a biochemical classification of depressive disorders. II. Application of multivariate
discriminant function analysis to data on urinary catecholamines and metabolites.
Arch Gen Psychiatry 1978 Dec;35(12):1436-9
"The previous article in this
series reported on the differences in urinary excretion of 3-methoxy-4-hydroxyphenylglycol
(MHPG) in patients with various clinically defined subtypes of depressive disorders.
We now report that further biochemical discrimination among depressive subtypes
is provided by the following equation, derived empirically by applying multivariate
discriminant function analysis to data on urinary catecholamine metabolits: Depression-type
(D-type) score = C1(MHPG) + C2(VMA) + C3(NE) +C4(NMN + MN)/VMA + C0. In the original
derivation of this equation, low scores were related to bipolar manic-depressive
depressions, and high scores were related to unipolar nonendogenous (chronic characterological)
depressions. Findings from a series of depressed patients whose biochemical data
had not been used to derive this equation confirmed these differences in D-type
scores among subtypes of depressions. The findings presented in this report further
suggest that we can discriminate three biochemically discrete subgroups of depressive
F, Maas JW, Dekirmenjian H, Sanchez J.
Diagnostic subgroups of affective
disorders and their urinary excretion of catecholamine metabolities.
Am J Psychiatry 1975 Nov;132(11):1141-8
"Previous reports have indicated
that some depressed patients excrete less than normal quantities of 3-methoxy-4-hydroxyphenyl
glycol (MHPG). The authors present data indicating that a subgroup of depressed
patients who excrete less than normal quantities of MHPG may be identified by
the application of explicit clinical criteria. They found no significant difference
in the excretion of normetanephrine (NM), metanephrine (M), and 3-methoxy-4-hydroxymandelic
acid (VMA) among any of the diagnostic subgroups or between each patient group
and a healthy comparison group. However, depressed patients diagnosed as having
primary affective disorder and bipolar illness excreted significantly less MHPG
than did the healthy comparison group." [Abstract]
Symptom patterns in unipolar and bipolar depression correlating
with monoamine metabolites in the cerebrospinal fluid: II. Suicide.
Res 1980 Oct;3(2):225-36
"Suicidality scores from the Schedule for Affective
Disorders and Schizophrenia on 21 unipolar and 12 bipolar depressives were correlated
with monoamine metabolites in the cerebrospinal fluid using multiple regression
analyses. The single item of Suicidal Tendencies Worst Week correlated highly
significantly and negatively with 3-methoxy-4-hydroxyphenylglycol (MHPG) and only
to a very slight degree with 5-hydroxyindoleacetic acid (5HIAA). Seriousness of
Intent of Worst Suicide Attempt earlier in life correlated significantly and negatively
with both MHPG and 5HIAA. Subjective Anger was positively and Overt Anger negatively
associated with thoughts of suicide. The results support earlier reports that
depressives with low 5HIAA are prone to violent suicides, but also point to the
equal, if not even greater involvement of MHPG and noradrenergic neuronal systems
in carrying out a wish for death." [Abstract]
Garfinkel PE, Warsh JJ, Stancer HC, Godse DD.
CNS monoamine metabolism in bipolar affective disorder. Evaluation
using a peripheral decarboxylase inhibitor.
Arch Gen Psychiatry
"Carbidopa, a decarboxylase inhibitor that does
not cross the blood-brain barrier, inhibits the peripheral synthesis of nor-adrenaline,
serotonin, and tryptamine. By reducing the peripheral component of end-products
of these amines in urine, a more accurate assessment of central nervous system
(CNS) amine metabolism is provided. Urinary 5-hydroxyindoleacetic acid (5-HIAA),
tryptamine, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured over ten
days in ten normal controls and eight bipolar depressives. After a three-day baseline
period, carbidopa, 100 mg three times a day, was given for seven days. While the
patients tended to excrete less MHPG in the baseline period, these differences
became somewhat larger, and statistically significant when peripheral contributions
were reduced with carbidopa. While carbidopa resulted in striking inhibition of
tryptamine excretion, and smaller decreases in the excretion of 5-HIAA and MHPG,
evidently from storage pools, there were no significant differences in degree
of inhibition between patients and controls. Absolute values of 5-HIAA and tryptamine
were similar for both groups, during the baseline and again with carbidopa. These
results after carbidopa are compatible with a central catecholaminergic deficit
in bipolar depressives and the use of urinary MHPG as an index of CNS catecholamine
Beckmann H, Goodwin FK.
Urinary MHPG in subgroups
of depressed patients and normal controls.
"3-Methoxy-4-hydroxyphenylglycol (MHPG), the urinary
metabolite thought best to reflect brain norepinephrine metabolism, was studied
in a large group of hospitalized depressed patients with primary affective disorder
and in normal controls, as part of an ongoing effort to evaluate the role of central
amine dysfunction in affective illness. Overall there was no difference in MHPG
between the depressed patients and controls. Hosever, within the depressed population
the bipolar patients excreted significantly less MHPG than the unipolars and,
as a group, the male bipolar patients had significantly lower MHPG than male controls.
MHPG correlated positively with age, age of onset, rating of anxiety and psychosis
and, most importantly, with systolic blood pressure. These data support the concept
of biological heterogeneity among individuals with major depressive disorders.
However, the relationship between MHPG excretion and various psychological and
physiological parameters is both intriguing and complex and warrants careful interpretation."
MV, Ross RJ, Linnoila M, Sherer MA, Potter WZ.
responsivity of plasma norepinephrine in depression.
Gen Psychiatry 1985 Dec;42(12):1186-92
"An orthostatic challenge paradigm
was used to assess noradrenergic regulation in depressive disorders. Plasma norepinephrine
(NE) concentrations and concurrent blood pressure and pulse were measured at rest
and after five minutes of standing in groups of bipolar (N = 22) and unipolar
(N = 19) depressives and in 12 partially age-matched healthy female volunteers.
Supine plasma NE levels were significantly lower in bipolar patients than in either
unipolar depressives or normal volunteers. Following the orthostatic challenge,
the fractional NE increase in both patient groups--particularly the bipolar group--was
greatly exaggerated, exceeding that in the controls by approximately 100%. Nonetheless,
the postural cardiovascular changes--elevations of diastolic blood pressure and
heart rate--failed to distinguish the three subject groups. Noradrenergic dysregulation
in depression thus is characterized by inefficient hyperreactivity to physiologic
F, Potter WZ.
Catecholamines in depression: a cumulative study
of urinary norepinephrine and its major metabolites in unipolar and bipolar depressed
patients versus healthy volunteers at the NIMH.
Res 1999 Jul 30;87(1):21-7
"Studies comparing urinary norepinephrine
(NE) and its metabolites in unipolar or bipolar depressed patients and healthy
volunteers have not yielded consistent findings. However, in unipolar depressed
patients, most studies in non-elderly populations consistently report elevated
concentrations of plasma NE, at least following an orthostatic challenge. Expanding
upon previous studies which showed elevated plasma NE in depression, we compared
the urinary excretion of NE, normetanephrine (NMN), 3-methoxy-4-hydroxyphenylglycol
(MHPG), and vanillylmandelic acid (VMA) in age- and sex-matched unipolar and bipolar
depressed patients versus healthy volunteers hospitalized at an inpatient unit
at the National Institute of Mental Health. Only depressed subjects with a minimum
4-week drug-free period were included. Total turnover (NE + NMN + MHPG + VMA)
was reduced in this sample of unipolar and bipolar depressed patients. MHPG concentration
did not distinguish unipolar from bipolar depressed patients and was not significantly
different from that in healthy volunteers. A construct of the average fractional
extraneuronal concentration of NE (NE + NMN/NE + NMN + MHPG + VMA) was significantly
higher in unipolar and bipolar depressed patients than in healthy volunteers.
This finding extends data suggesting that unmedicated unipolar and bipolar depressed
patients have a 'hyperresponsive' noradrenergic system and provides a framework
which ties together plasma and urinary findings." [Abstract]
DF, Shen YC, Shu LN, Lo HC.
Dexamethasone suppression test and
urinary MHPG X SO4 determination in depressive disorders.
Biol Psychiatry 1987 Jul;22(7):883-91
"The Dexamethasone Suppression
Test (DST) was performed in 64 depressed inpatients, in 48 schizophrenics, and
in 20 normal controls. Thirty-four percent of depressive inpatients were found
to escape from dexamethasone suppression significantly higher than either schizophrenics
(13%) or normal subjects (5%). Among subgroups, bipolar and unipolar endogenous
depression patients had much higher abnormal rates for the DST (59% and 48%, respectively)
than nonendogenous cases (8%). DST results were also found to be positively correlated
with patients' Hamilton scores. These findings suggested that DST could be helpful
in diagnosis, discrimination of subtypes, and in assessment of severity of symptoms.
In 32 of the 64 depressed inpatients, urinary MHPG X SO4 excretion was determined
and compared with 21 normal controls. Bipolar patients (n = 7) had less MHPG X
SO4 excretion than unipolar endogenous patients (n = 16). Excretion was positively
correlated with cortisol level at 17 hr after dexamethasone administration in
32 depressive inpatients, especially in the unipolar subgroup. A trend toward
negative correlation, though not statistically significant, was found in bipolar
depression between cortisol levels at 17 hr after dexamethasone administration
and urinary MHPG X SO4 excretion. This may indicate that some differences in norepinephrine
(NE) metabolism may exist between unipolar and bipolar depression, leading to
differing correlations between deviation of central NE function and hypothalamus-pituitary-adrenal
(HPA) axis in different subgroups of depression." [Abstract]
B, Loo H, Dennis T, Benkelfat C, Gay C, Poirier-Littre MF.
in plasma levels of 3,4-dihydroxyphenylethyleneglycol in major depression.
Psychopharmacology (Berl) 1986;88(2):220-5
"Plasma levels of free and
sulfoconjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the main deaminated
metabolite of norepinephrine, were measured in a group of 45 hospitalized patients
presenting a major depression and a group of 45 healthy subjects, matched for
sex and age. Compared to healthy subjects, depressed patients had significantly
lower plasma levels of free and sulfoconjugated DOPEG. The ratio of free over
conjugated DOPEG was not statistically different in the two groups. The reduction
of plasma DOPEG levels in the depressed patients did not appear to be related
to the duration of drug-free period and was similar in males and females. There
was no statistically significant correlation between plasma DOPEG levels and total
score on the Hamilton Rating Scale for Depression. Finally, plasma DOPEG levels
did not differ in uni or bipolar patients. The present data provides further evidence
for a reduced CNS noradrenergic transmission in major depression." [Abstract]
Swann AC, Secunda S, Davis JM, Robins E, Hanin
I, Koslow SH, Maas JW.
CSF monoamine metabolites in mania.
Am J Psychiatry 1983 Apr;140(4):396-400
"As part of the
National Institute of Mental Health Clinical Research Branch Collaborative Program
on the Psychobiology of Depression, the authors compared concentrations of CSF
monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol
[MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite
5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with
concentrations from 62 healthy comparison subjects. The manic patients had significantly
higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic
patients and the comparison male subjects, but they were elevated in the female
manic patients. MHPG was the only metabolite that correlated significantly with
mania symptom ratings. These data are consistent with findings that have shown
abnormal, perhaps excessive, central noradrenergic activity in patients with mania,
but not with those suggesting deficits in serotoninergic function." [Abstract]
RM, Rubinow DR, Uhde TW, Roy-Byrne PP, Linnoila M, Rosoff A, Cowdry R.
Dysphoric mania. Clinical and biological correlates.
Arch Gen Psychiatry 1989 Apr;46(4):353-8
"Patients studied at peak severity
of a manic episode showed substantial degrees of depression (dysphoria) and anxiety.
Compared with nondysphoric manics (n = 26), the dysphoric manics (n = 22) had
a significantly greater number of previous hospitalizations, and they displayed
less rapid cycling both in the year before and during the index hospitalization
admission. The severity of manic dysphoria tended to correlate with the number
of previous hospitalizations, a finding that was highly significant in women (n
= 27). Medication-free manic patients (n = 22) had significant elevations in cerebrospinal
fluid norepinephrine concentrations compared with depressed and euthymic patients
and normal volunteers, and the degree of elevation correlated significantly with
the degree of manic dysphoria, anger, and anxiety rated at the time of the lumbar
puncture. Patients with dysphoric mania, recognized by Kraepelin to have poor
prognoses, have been reported to respond poorly to lithium carbonate but may be
among those who respond to carbamazepine. Clinical, biologic, and pharmacologic
response characteristics of manic subgroups, particularly those with extreme dysphoric
components to their illness, appear to be clinically meaningful and deserving
of further investigation." [Abstract]
AC, Secunda SK, Koslow SH, Katz MM, Bowden CL, Maas JW, Davis JM, Robins E.
Mania: sympathoadrenal function and clinical state.
Psychiatry Res 1991 May;37(2):195-205
"We investigated sympathoadrenal
and sympathetic nervous system activity, catecholamine disposition, and clinical
state in 19 hospitalized manic patients. Severity of the core manic syndrome,
anxiety, and hostility correlated with 24-hour urinary excretion of epinephrine
relative to its metabolites, but only weakly with norepinephrine. Agitation, however,
correlated most strongly and significantly with norepinephrine. Eight of the patients
had mixed states: concurrent manic and depressive syndromes. There were no differences
between mixed and pure manic patients with respect to catecholamine or metabolite
excretion or precursor/product ratios, but mixed manic patients tended to have
higher excretion of norepinephrine and had increased variance with respect to
catecholamine measures. These data suggest that the function of the adrenal medulla,
whether directly or indirectly, is important in the symptoms of both mixed and
pure mania." [Abstract]
NH, Margolese HC, Saint-Laurent M, Chouinard G.
Dysphoric mania induced
by high-dose mirtazapine: a case for 'norepinephrine syndrome'?
Clin Psychopharmacol 2002 Nov;17(6):319-22
"The antidepressant mirtazapine
antagonizes central presynaptic alpha2-adrenergic auto- and heteroreceptors resulting
in increased central norepinephrine and serotonin activity. Histamine H2 receptors
are also antagonized, as are postsynaptic serotonin 5-HT2 and 5-HT3 receptors,
leading to serotonergic activity primarily via 5-HT1A receptors. Based on the
case report of a patient who developed mania with higher than recommended dosage
of mirtazapine, we review the literature on the atypical nature of manic symptoms
with mirtazapine. Eight subjects, including those in our study, were identified
as having developed mirtazapine-induced mania with atypical features, consisting
of dysphoria, irritability, insomnia, psychomotor agitation and abnormal gait.
Predisposing features may have included the presence of underlying brain dysfunction
and certain selective serotonin reuptake inhibitor-mirtazapine combinations. Dysphoric
mania with atypical features may be induced by mirtazapine, providing support
for a common hypothesis such as 'central norepinephrine hyperactivity' as the
basis for development of mania with mirtazapine." [Abstract]
AC, Stokes PE, Secunda SK, Maas JW, Bowden CL, Berman N, Koslow SH.
Depressive mania versus agitated depression: biogenic amine and hypothalamic-pituitary-adrenocortical
Biol Psychiatry 1994 May 15;35(10):803-13
"The existence of mixed affective states challenges the idea of specific
biological abnormalities in depression and mania. We compared biogenic amines
and hypothalamic-pituitary-adrenocortical (HPA) function in mixed manic (n = 8),
pure manic (n = 11), agitated bipolar depressed (n = 20), and nonagitated bipolar
depressed (n = 27) inpatients (Research Diagnostic Criteria). Mixed manics met
Research Diagnostic Criteria for primary manic episodes and also met criteria
for major depressive episodes except for duration. The norepinephrine metabolite
methoxyhydroxy phenthylene glycol (MHPG) was higher in cerebrospinal fluid from
mixed manic than from agitated depressed patients, consistent with differences
previously reported between the overall samples of depressed and manic patients.
Similarly, patients in a mixed state had higher urinary excretion of norepinephrine
(NE) and elevated output of NE relative to its metabolites. HPA activity was similar
in mixed manic and agitated depressed patients. These data suggest that mixed
manics combine certain biological abnormalities considered to be characteristic
of mania and of depression." [Abstract]
LE, Gerhardt GA, Franks R, Baker N, Nagamoto H, Drebing C, Freedman R.
physiology and catecholamines in schizophrenia and mania.
Psychiatry Res 1990 Mar;31(3):297-309
"Hypersensitivity to sensory stimulation
is a prominent characteristic of both schizophrenia and mania. Neurophysiological
recordings suggest a common deficit in a central neuronal sensory gating mechanism
which regulates sensitivity to repeated auditory stimuli. Dopamine and norepinephrine
are hypothesized to have major roles in these illnesses, but their role in aberrant
sensory processing has not yet been proved. Presumptive evidence for effects of
catecholamines on sensory processing comes from psychophysiological studies of
normal subjects challenged with stimulants who show decreased sensory gating,
and studies of psychotic patients treated with neuroleptics who show improved
function. Studies of similar phenomena in animals show comparable effects of catecholamines
on sensory processing, both behaviorally and at the single neuron level. In this
study, gating of auditory evoked potentials (EPs) during treatment of both illnesses
was compared with plasma dopamine and norepinephrine metabolites. Comparisons
of medicated and unmedicated states showed that schizophrenic patients have a
fixed deficit in sensory gating, which is a familial trait, unchanged by medication.
During acute illness, they have an additional transient hypersensitivity to stimuli,
manifested as smaller EPs, which seems to be mediated by dopamine. Manic patients
have only the deficit in sensory gating, which is transient and seems to be mediated
by norepinephrine. Thus, similar neurophysiological deficits in the two psychoses
are associated with different biochemical abnormalities, which may explain similarities
in acute symptoms and differences in other aspects of the illnesses, such as their
response to treatment." [Abstract]
AC, Petty F, Bowden CL, Dilsaver SC, Calabrese JR, Morris DD.
gender, transmitter function, and response to treatment.
Psychiatry Res 1999 Oct 18;88(1):55-61
"Noradrenergic and GABA systems
may be involved in mania, but there is little information about relationships
between the function of these systems and response to specific antimanic treatments.
We investigated relationships between indices of catecholamine or GABA system
function, pretreatment mania severity and antimanic response to divalproex, lithium,
or placebo. Plasma GABA and urinary excretion of catecholamine metabolites were
measured before randomization to lithium, divalproex or placebo in patients hospitalized
for manic episodes. Severity of mania was evaluated using the Manic Syndrome,
Behavior and Ideation and Mania Rating Scale scores from the SADS-C. Multiple
regression analysis showed that pretreatment plasma GABA was related to severity
of manic symptoms. This relationship seemed stronger in women. Multiple regression
analysis showed that pretreatment levels of urinary MHPG correlated with improvement
in manic syndrome scores. These data suggest that GABA and norepinephrine may
be related to different aspects of the manic state and to its pharmacologic sensitivity."
Swann AC, Berman N, Frazer A, Koslow SH, Secunda S.
Lithium distribution in mania: plasma and red blood cell lithium, clinical
state, and monoamine metabolites during lithium treatment.
Psychiatry Res 1987 Jan;20(1):1-12
"We examined red blood cell (RBC)
and plasma lithium concentrations and RBC/plasma lithium ratios in 14 manic patients
during lithium treatment as part of the National Institute of Mental Health's
Collaborative Program on the Psychobiology of Depression, Biological Studies.
All of the lithium measures increased during treatment, especially RBC lithium.
There were positive correlations between the RBC lithium concentration and the
RBC/plasma lithium ratio and their maximal values in a single-dose pharmacokinetic
experiment before treatment. After 5 and 16 days of treatment, patients with good
subsequent outcome had higher RBC/plasma lithium ratios than did patients with
poor outcome. Early in treatment, there was a negative correlation between lithium
concentrations and severity of mania. During treatment, there was a negative correlation
between RBC lithium and urinary MHPG excretion. There was a positive correlation
between RBC or plasma lithium during the first few days of treatment and subsequent
reduction in norepinephrine excretion during treatment. At 3 weeks, there were
negative correlations between reductions in catecholamine measures and lithium
concentrations. These data suggest that there are changes in the sensitivity of
behavior and catecholamine function to lithium during treatment. RBC concentrations
of lithium appear to be a potentially useful indicator of its behavioral and neurochemical
AC, Koslow SH, Katz MM, Maas JW, Javaid J, Secunda SK, Robins E.
carbonate treatment of mania. Cerebrospinal fluid and urinary monoamine metabolites
and treatment outcome.
Arch Gen Psychiatry 1987 Apr;44(4):345-54
"Treatment of manic patients with lithium carbonate was associated with significant
decreases in cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG)
and urinary norepinephrine excretion. These measures, before treatment, were higher
in manic patients than in either depressed or normal subjects and correlated significantly
with severity of mania. Levels in CSF of homovanillic acid and 5-hydroxyindoleacetic
acid did not correlate with severity or with change during lithium carbonate treatment.
Responders (about 70% of the patients) did not differ from nonresponders in pretreatment
mania ratings or neurotransmitter measures. The CSF MHPG and urinary norepinephrine
excretion were reduced during lithium carbonate treatment in both responders and
nonresponders. Unlike the case before treatment, urinary MHPG excretion was higher
during treatment in nonresponders than in responders and correlated with several
indexes of symptom severity. These results support a relationship between mania
and increased noradrenergic function. Treatment outcome, however, was not related
exclusively to the reduction of noradrenergic indexes by lithium carbonate since
reductions were similar in both responders and nonresponders. Reduced noradrenergic
activity may therefore be necessary but not sufficient for successful outcome
during lithium carbonate treatment." [Abstract]
H, ST-Laurent J, Goodwin FK.
The effect of lithium on urinary MHPG
in unipolar and bipolar depressed patients.
1975 Jun 19;42(3):277-82
"Twenty-four hour urinary excretion of 3-methoxy-4-hydroxphaeylglycol
(MHPG), the metabolite thought best to reflect brain norepinephrine metabolism,
was studied longitudinally in ten depressed patients before and during the acute
and chronic phases of lithium treatment. Five of the patients were identified
as bipolar I (prior history of mania), 3 as bipolar II (history of hypomania)
and 2 as unipolar (history of depression). During acute lithium administration
(first week) there was no consistent pattern of change in MHPG. Comparing the
predrug period with the third and fourth week of treatment, all of the responders
showed an increase in MHPG, while the non-responders showed no change or a decrease.
It is concluded that the change in clinical state is the most important variable
contributing to MHPG changes in these patients. There was a tendency for the pretreatment
MHPG excretion to be low in the patients who went on to show a clear-cut antidepressant
response to lithium compared to those who were unequivocal non-responders. The
predrug MHPG for the bipolar patients (prior history of mania) was significantly
lower than the unipolar patients, a difference which apparently contributes to
the lower MHPG in the lithium responders, all of whom were in the bipolar group."
PJ, Dominguez RA, DeVane CL, Bowden CL.
Bupropion slow-release response
in depression: diagnosis and biochemistry.
1998 Oct 1;44(7):629-32
"BACKGROUND: Bupropion has been previously shown
to be particularly beneficial in bipolar and atypical depression. Previous research
has supported a possible association of response to plasma levels and to changes
in plasma homovanillic acid (HVA). These findings were here extended to bupropion
slow-release (SR), a formulation with slower release kinetics. METHODS: Forty-one
patients with major depressive disorder (DSM-III-R) completed 8 weeks of a fixed
dose of 300 mg/day in two doses/day. Clinical outcome measures were the Hamilton
Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). Biological
parameters included plasma HVA and 3-methoxy-4-hydroxyphenyl-glycol (MHPG), as
well as a final measurement of plasma bupropion and its metabolites. RESULTS:
Response to bupropion SR differed among the three groups: results for change in
HDRS and in BDI were greater in the bipolar and atypical than in the "typical"
depressed patients. Mean change in HDRS was, respectively, of 15.6, 17.1, and
7.6 (F = 5.57, p < .01); mean change in the BDI, 21.1, 16.9, and 7.3 (F = 3.32,
p < .05). Threobupropion levels correlated with HDRS scores (r = .47, p = .02,
n = 23); plasma HVA and MHPG increased significantly (t = 2.31, p = .03; t = 2.15,
p = .04, n = 17). Bipolar depressed patients' improvement in HDRS was related
to increases in MHPG (r = .87, p = .01) and in HVA (r = .70, p = .08). CONCLUSIONS:
This fixed-dose study indicates that there may be specific benefits for bupropion
SR in atypical and bipolar depression, and that these benefits may be related
also to plasma levels and biochemical changes in catecholamines. Due to the small
sample size, replication is of key importance." [Abstract]
Bakchine S, Lacomblez L, Benoit N, Parisot D, Chain F, Lhermitte
Manic-like state after bilateral orbitofrontal and right temporoparietal
injury: efficacy of clonidine.
Neurology 1989 Jun;39(6):777-81
"A manic-like state occurred in a 44-year-old right-handed woman with bilateral
orbitofrontal and right temporoparietal traumatic contusions. In a brief trial,
we assessed the effect of clonidine, carbamazepine, dopa therapy, and placebo
on manic symptoms and cognitive functions. Clonidine rapidly reversed the manic
syndrome. The patient's behavior did not change with carbamazepine and worsened
with levodopa. We suggest that the manic-like syndrome was related to noradrenergic
overactivity secondary to the fronto-orbital lesions." [Abstract]
Time course of clinical effects of carbamazepine: implications
for mechanisms of action.
J Clin Psychiatry 1988 Apr;49
"The relatively acute time course of antimanic efficacy may
be related to the above-mentioned mechanisms or to other effects related to systems
postulated to be altered in the manic syndrome. These effects might include carbamazepine's
ability to increase acetylcholine in the striatum, decrease probenecid-induced
levels of CSF homovanillic acid (HVA) in man and dopamine turnover in animals,
decrease CSF norepinephrine in manic patients, inhibit adenylate cyclase activity
(in response to norepinephrine, dopamine, adenosine, or ouabain), decrease GABA
turnover, or act as a vasopressin agonist." [Abstract]
AC, Secunda SK, Stokes PE, Croughan J, Davis JM, Koslow SH, Maas JW.
Stress, depression, and mania: relationship between perceived role of stressful
events and clinical and biochemical characteristics.
Psychiatr Scand 1990 Apr;81(4):389-97
"We investigated the perceived
role of stressful events in episodes of major affective disorder in patients studied
in the NIMH Clinical Research Branch Collaborative Program on the Psychobiology
of Depression (Biological Studies). Using items from the Schedule for Affective
Disorders and Schizophrenia (SADS), episodes were divided into environment-sensitive
(high perceived role of stressful events) and autonomous (minimal or no perceived
role of stressful events). Patients with environment-sensitive episodes had fewer
previous episodes and a longer index episode. The groups did not differ with respect
to age, gender, education, socioeconomic group, diagnosis, severity of illness,
or eventual response to treatment. Unipolar depressed patients with environment-sensitive
episodes had lower CSF 5-HIAA than those with autonomous episodes. Among bipolar
depressed patients, those with autonomous episodes had elevated excretion of O-methylated
catecholamine metabolites and of epinephrine, while those with environment-sensitive
episodes had normal excretion of catecholamines and metabolites. Manic subjects
with environment-sensitive episodes had elevated norepinephrine excretion, while
this was normal in manics with autonomous episodes. Relationships between environmental
sensitivity of affective episodes and neurotransmitter function therefore appear
to be related to the type of episode." [Abstract]
TR, Mason JW, Giller EL, Ostroff RB, Harkness L.
norepinephrine and epinephrine elevation in post-traumatic stress disorder.
"Urinary norepinephrine and
epinephrine levels (microgram/day) were measured at two-week intervals during
the course of hospitalization in the following patient groups: post-traumatic
stress disorder (PTSD); major depressive disorder (MDD); bipolar I, manic (BP);
paranoid schizophrenia (PS); and undifferentiated schizophrenia (US). The mean
norepinephrine level during hospitalization was significantly higher in PTSD (76
+/- 10.4 micrograms/day) than in BP (60.6 +/- 8.4 micrograms/day), MDD (41.2 +/-
4.7 micrograms/day), PS (33.4 +/- 4.9 micrograms/day) and US (34.3 +/- 5.9 micrograms/day)
groups, according to Duncan's multiple range test, (F(4,39) = 6.94, p less than
0.0003). The norepinephrine elevations in the PTSD group were sustained throughout
hospitalization. The only other group to show mean levels in this range was the
BP group in the first sample after hospital admission. This finding supports prior
psychophysiological studies indicating increased sympathetic nervous system activity
in PTSD patients. The mean epinephrine level during hospitalization was also significantly
higher in PTSD (22.7 +/- 2.4 micrograms/day) than in MDD (13.6 +/- 1.7 micrograms/day),
PS (14.7 +/- 2.4 micrograms/day), and US (18.9 +/- 1.8 micrograms/day), but not
higher than in BP (21.5 +/- 2.7 micrograms/day). The relationship of epinephrine
levels among diagnostic groups was sustained throughout hospitalization. It appears
likely that the main underlying mechanisms for elevations of both hormones are
psychological, but further work will be required to establish the exact nature
of these mechanisms." [Abstract]
Young LT, Warsh JJ, Kish SJ, Shannak K, Hornykeiwicz
Reduced brain 5-HT and elevated NE turnover and metabolites
in bipolar affective disorder.
Biol Psychiatry 1994 Jan
"Levels of norepinephrine (NE), serotonin (5-HT), dopamine
(DA), and their major metabolites were determined in postmortem brain obtained
from nine subjects with antemortem histories meeting DSM-III-R criteria for bipolar
affective disorder. Compared with controls, no statistically significant differences
were found in mean levels of NE, 5-HT, or DA in any brain area of bipolar subjects.
NE turnover as estimated by the ratio of the major NE metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol
(MHPG) to NE was increased in frontal (+107%), temporal (+103%), and occipital
(+64%) cortex and thalamus (+83%). Significant decreases were found in the major
5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA), in frontal (-54%) and parietal
cortex (-64%), and in 5-HIAA/5-HT ratio in temporal cortex (-55%), with a trend
for decreases in both measures in caudate nucleus. In addition, levels of the
major DA metabolite, homovanillic acid (HVA) were significantly decreased (-46%)
in parietal cortex and HVA/DA ratios were significantly reduced (-66%) in occipital
cortex obtained from bipolar compared to control subjects. Our data, taken together
with previous findings regarding monoamines in postmortem brain of depressed and
suicide subjects, suggest that decreased 5-HT metabolite levels and turnover may
be common to all mood disorders. Increased cortical NE turnover, however, may
be a more important component in the pathophysiology of bipolar disorder."
[Note that no information on the mood state of the subjects is given.]
SC, Minkus D, Swann AC.
Chronic treatment with valproate decreases
the hypothermic response to clonidine.
Behav 1993 May;45(1):247-9
"Treatment with lithium (the prototype of
an antimanic agent) attenuates responsiveness to the alpha 2-agonist clonidine
in animal models. Valproate is now used to treat mania. The effect of treatment
with this drug on responses mediated by an alpha 2-agonist have yet to be reported.
The authors assessed the effect of a 14-day course of orally administered valproate
on the rat's hypothermic response to clonidine. Treatment with valproate decreased
this response." [Abstract]
M, London ED, Silverman DH, Rasgon N, Kirchheiner J, Whybrow PC.
brain and mood modulation in affective disorder: insights from molecular research
and functional brain imaging.
Pharmacopsychiatry. 2003 Dec;36
"The efficacy resulting from adjunctive use of supraphysiological
doses of levothyroxine has emerged as a promising approach to therapy and prophylaxis
for refractory mood disorders. Most patients with mood disorders who receive treatment
with supraphysiological doses of levothyroxine have normal peripheral thyroid
hormone levels, and also respond differently to the hormone and tolerate it better
than healthy individuals and patients with primary thyroid diseases. Progress
in molecular and functional brain imaging techniques has provided a new understanding
of these phenomena, illuminating the relationship between thyroid function, mood
modulation and behavior. Thyroid hormones are widely distributed in the brain
and have a multitude of effects on the central nervous system. Notably many of
the limbic system structures where thyroid hormone receptors are prevalent have
been implicated in the pathogenesis of mood disorders. The influence of the thyroid
system on neurotransmitters (particularly serotonin and norepinephrine), which
putatively play a major role in the regulation of mood and behavior, may contribute
to the mechanisms of mood modulation. Recent functional brain imaging studies
using positron emission tomography (PET) with [ (18)F]-fluorodeoxyglucose demonstrated
that thyroid hormone treatment with levothyroxine affects regional brain metabolism
in patients with hypothyroidism and bipolar disorder. Theses studies confirm that
thyroid hormones are active in modulating metabolic function in the mature adult
brain, and provide intriging neuroanatomic clues that may guide future research."