Gerner RH, Fairbanks L, Anderson GM, Young JG, Scheinin M, Linnoila
M, Hare TA, Shaywitz BA, Cohen DJ.
CSF neurochemistry in depressed,
manic, and schizophrenic patients compared with that of normal controls.
J Psychiatry 1984 Dec;141(12):1533-40
"A total of 114 subjects (41 depressed,
20 schizophrenic, 15 manic, and 38 normal controls) underwent lumbar puncture
and their CSF was analyzed for levels of tyrosine, tryptophan, homovanillic acid
(HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG),
choline, gamma-aminobutyric acid (GABA), and calcium. Results showed that depressed
patients, particularly those over 40 years of age, had lower levels of GABA than
did controls, and that their level of HVA increased with age, while controls'
decreased. Schizophrenic subjects tended to have higher levels of 5-HIAA and manic
subjects tended to have higher levels of HVA and MHPG. Age-associated changes
were found in HVA, 5-HIAA, MHPG, GABA, and choline concentrations." [Abstract]
Tandon R, Channabasavanna SM, Greden JF.
biochemical correlates of mixed affective states.
Scand 1988 Sep;78(3):289-97
"To evaluate the question of whether "mixed"
bipolar disorder is a distinct entity, we compared selected cerebrospinal fluid
(CSF) biochemical parameters from patients with bipolar disorder, mixed, to those
with mania and major depression. Fourteen patients in each category (DSM-III)
were studied with regard to CSF HVA, 5HIAA, sodium, potassium, calcium, and magnesium
levels under carefully controlled conditions. CSF HVA, 5HIAA, and sodium were
found to be significantly higher in manics than in major depressives. Discriminant
analysis of the biochemical variables of the mixed affective group identified
two biochemically distinct and clinically different subgroups of seven patients
each, one resembling the manic group and the other the major depressive group."
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
JC, Czobor P, Tuma I, Charles O, Bebe R, Cooper TB, Chang WH, Lane HY, Stone DL.
plasma HVA and haloperidol response in acute mania.
Disord. 2000 Jul;59(1):55-9.
"INTRODUCTION: Pretreatment plasma homovanillic
acid (HVA) levels have been reported to be a correlate of clinical response to
typical antipsychotics for schizophrenic, bipolar manic, and mixed groups of psychotic
patients. Biological markers of clinical response to antipsychotics could be useful
for optimizing drug treatment. METHOD: Thirty-one consenting acute inpatient subjects
between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder,
manic with psychotic features were entered into this double-blind study and were
randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg
for the 3-week study. Subjects also received one of the following concomitant
medications: standard lithium, lorazepam 4 mg/day, or placebo. RESULTS: The primary
multiple regression analysis, including all subjects on both haloperidol doses,
yielded a significant main effect for pretreatment plasma HVA (n=31, F=5.7, P=0.025),
indicating that higher pretreatment plasma HVA was predictive of better clinical
response. In addition, the interaction between haloperidol dose and pretreatment
plasma HVA was also significantly associated with clinical response (F=12.59,
P=0.0015). When the two haloperidol doses were analyzed separately, we found that
pretreatment plasma HVA was only correlated with clinical response in the low
haloperidol 5 mg/day group (n=18, F=11.73, P=0.0038) and was unrelated to clinical
response to the high haloperidol 25 mg/day group. LIMITATIONS: The sample size
was small. Results may have been confounded by prior antipsychotic treatment and
concomitant use of lithium or lorazepam. DISCUSSION: These results suggest that
pretreatment plasma HVA could be useful for dosing antipsychotics. Patients with
high plasma HVA levels would be good candidates for low-dose treatment because
they are more likely to improve on such a dose, while patients with low plasma
HVA levels might warrant more rapid dosage escalation." [Abstract]
Fortunati F, Mazure C, Preda A, Wahl R, Bowers M
Plasma catecholamine metabolites in antidepressant-exacerbated
mania and psychosis.
J Affect Disord 2002 Apr;68(2-3):331-4
measured plasma free HVA and MHPG in 39 cases of psychosis or mania judged to
be caused by antidepressant exacerbation of symptoms. A total of 24 of patients
had been receiving selective serotonin reuptake inhibitors (SSRI's). The SSRI
group showed a pattern of increased plasma HVA similar to a comparison group of
patients with a psychotic/manic relapse secondary to medication non-compliance."
CM, Bowers MB.
Pretreatment plasma HVA predicts neuroleptic response
in manic psychosis.
J Affect Disord 1998 Feb;48(1):83-6
pretreatment plasma free homovanillic acid (HVA) predicted acute response to neuroleptic
treatment in patients with manic psychosis. These findings suggest that plasma
HVA may be a useful predictor of a successful short-term response in manic as
well as schizophrenic psychoses, and that elevated pre-synaptic dopaminergic release
may play a role in more than one group of psychotic disorders." [Abstract]
RM, Jimerson DC, Bunney WE Jr, Goodwin FK.
Dopamine and mania: behavioral
and biochemical effects of the dopamine receptor blocker pimozide.
"Although recent data suggest that pimozide
has effects at other neurotransmitter receptor sites, it is one of the more specific
neuroleptics in its effects on dopamine receptors. We report that in manic patients
pimozide produces substantial clinical improvement with a magnitude and time course
similar to that observed with the more routinely used phenothiazines chlorpromazine
and thioridazine. Pimozide did not significantly increase probenecid-induced accumulations
of the dopamine metabolite homovanillic acid (HVA) compared to pretreatment values.
Higher HVA values were observed in manic than in nonmanic patients, however. These
clinical and biochemical data add to a growing body of indirect evidence that
a dopaminergic alteration may be associated with some components of the manic
RH, Post RM, Bunney WE Jr.
A dopaminergic mechanism in mania.
J Psychiatry 1976 Oct;133(10):1177-80
"The authors present a case study
that explores the relationship of dopamine function and manic illness through
the use of two drugs with relatively specific effects in stimulating and blocking
dopamine receptors--piribedil (ET--495) and pimozide, respectively. Piribedil,
as well as d-amphetamine, was associated with manic episodes, while pimozide had
an antimanic effect. These observations suggest that dopaminergic mechanisms may
be involved in the mediation of manic episodes in at least some patients."
Amit, Verhoeff, Paul, Seneca, Nicholas, Zoghbi, Sami S., Seibyl,
John P., Charney, Dennis S., Innis, Robert B.
Brain SPECT Imaging
of Amphetamine-Induced Dopamine Release in Euthymic Bipolar Disorder Patients
Am J Psychiatry 2000 157: 1108-1114
"In a group of euthymic
patients with bipolar disorder, this study did not find evidence for increased
striatal dopamine release. Instead, these data are consistent with enhanced postsynaptic
dopamine responsivity in patients with bipolar disorder." [Abstract]
A, Davies RA, Hirst AD, Brown N, Papadopoulos A, Marks MN, Checkley SA, Kumar
RC, Campbell IC.
Menstrual cycle effects on hypothalamic dopamine
receptor function in women with a history of puerperal bipolar disorder.
Psychopharmacol. 2003 Jun;17(2):204-9.
"Neuroendocrine challenge tests
of hypothalamic dopamine receptor function in the early postpartum period suggest
that the sensitivity of these receptors is increased in women with a history of
bipolar disorder after childbirth. We tested the hypothesis that, in women predisposed
to bipolar disorder in the puerperium, hypothalamic dopamine receptor function
is more sensitive to changes in circulating ovarian hormone concentrations than
in women without such histories. Eight fully recovered and drug-free women who
had had at least one episode of bipolar illness following childbirth were compared
with nine normal controls. Growth hormone (GH) responses to apomorphine (APO 0.005
mg s.c.) were measured in the early follicular phase, when plasma concentrations
of ovarian hormones are low, and in the mid-luteal phase, when they are relatively
high. The recovered bipolar subjects and the controls did not differ from each
other in their follicular and midluteal oestrogen and progesterone concentrations.
In the midluteal phase, both groups had increased oestrogen and progesterone levels.
The recovered bipolar subjects did not differ from controls in baseline concentrations
of GH in either of the menstrual phases. The APO-GH responses of the two groups
did not differ in the follicular phase, but in the midluteal phase, when female
sex steroids are relatively increased, the recovered group had significantly enhanced
APO-GH responses [MANOVA for repeated measures: (i) area under the curve, group
by phase effect: p < 0.04; (ii) GH peak rise after APO, group by phase effect:
p < 0.056] and the responses were not related to concurrent measures of mood.
The results of this small study of women predisposed to bipolar disorder in the
puerperium shows an increased dopaminergic receptor sensitivity in the luteal
phase of the menstrual cycle. It suggests that their dopaminergic systems have
increased sensitivity to changes in circulating female sex steroids. This may
be aetiologically relevant to the pathogenesis of puerperal bipolar disorder."
Graf WD, Unis AS, Yates CM, Sulzbacher S, Dinulos
MB, Jack RM, Dugaw KA, Paddock MN, Parson WW.
Catecholamines in patients
with 22q11.2 deletion syndrome and the low-activity COMT polymorphism.
2001 Aug 14;57(3):410-6
"OBJECTIVE: To investigate catecholamine phenotypes
and the effects of a tyrosine hydroxylase inhibitor in individuals with the 22q11.2
deletion syndrome and low-activity catechol-O-methyltransferase (COMT). BACKGROUND:
Many persons with the 22q11.2 deletion syndrome suffer severe disability from
a characteristic ultrarapid-cycling bipolar disorder and associated "affective
storms." One etiologic hypothesis for this condition is that deletion of
the COMT gene from one chromosome 22 results in increased catecholamine neurotransmission,
particularly if the undeleted chromosome 22 encodes a variant of COMT with low
activity. METHODS: In a preliminary study, plasma, urine, and CSF catecholamines
and catecholamine metabolites were measured in four teenage patients with a neuropsychiatric
condition associated with 22q11.2 deletion and the low-activity COMT polymorphism
on the nondeleted chromosome. In these four patients, and an additional institutionalized
adult with the condition, an uncontrolled, open-label trial of metyrosine was
administered in an attempt to lower catecholamine production and to alleviate
symptoms. RESULTS: Mild elevations of baseline CSF homovanillic acid (HVA) were
found in three of four patients and a moderate reduction in CSF HVA after metyrosine
treatment in the patient with the highest pretreatment concentration. The course
of the five patients during the clinical trial is described. CONCLUSIONS: In patients
with the 22q11.2 deletion syndrome and low-activity COMT, controlled studies of
pharmacologic agents that decrease catecholamine production, block presynaptic
catecholamine storage, or enhance S-adenosylmethionine, the cosubstrate of COMT,
are warranted." [Abstract]
M, Karoum F, Potter WZ.
Effects of antidepressant treatments on dopamine
turnover in depressed patients.
Arch Gen Psychiatry 1983
"Effects of five antidepressant treatments--clorgyline,
desipramine hydrochloride, electroconvulsive treatment, lithium carbonate, and
zimelidine hydrochloride--on urinary outputs of dopamine, dihydroxyphenylacetic
acid, and homovanillic acid (HVA) were investigated in unipolar and bipolar depressed
patients. Clorgyline and lithium carbonate, which stabilized mood in bipolar patients,
reduced the urinary output of HVA and whole-body dopamine turnover. Electroconvulsive
treatment and zimelidine were without major effects, whereas desipramine had variable
effects on these indexes of dopamine metabolism. Three patients, two receiving
desipramine and one receiving clorgyline, who had increased HVA output during
the drug treatments, became severely agitated and delusional." [Abstract]
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
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]
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 S, Davis JM, Robins E, Hanin I, Koslow SH, Maas JW.
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]
PO, Undie AS, Kabbani N, Levenson R, Goldman-Rakic PS, Lidow MS.
of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic
and bipolar patients.
Proc Natl Acad Sci U S A. 2003 Jan
7;100(1):313-7. Epub 2002 Dec 20.
"The delineation of dopamine dysfunction
in the mentally ill has been a long-standing quest of biological psychiatry. The
present study focuses on a recently recognized group of dopamine receptor-interacting
proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients.
We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar
cases from the Stanley Foundation Neuropathology Consortium display significantly
elevated levels of the D2 dopamine receptor desensitization regulatory protein,
neuronal calcium sensor-1. These levels of neuronal calcium sensor-1 were not
influenced by age, gender, hemisphere, cause of death, postmortem period, alcohol
consumption, or antipsychotic and mood stabilizing medications. The present study
supports the hypothesis that schizophrenia and bipolar disorder may be associated
with abnormalities in dopamine receptor-interacting proteins." [Abstract]