Cardiovascular effects of 0.5 milligrams per kilogram oral d-amphetamine and possible attenuation by haloperidol

In a series of earlier studies, an oral dose of 0.5 mg/kg d-amphetamine was administered to 81 patients with schizophrenia and eight normal control subjects. Seven more subjects with schizophrenia received placebo. Blood pressure and pulse rate were monitored before and 3 hours after drug administration. Blood pressure increased in both amphetamine groups, whereas placebo had no effect. However, pulse rate did not change in the schizophrenic group and only increased after 3 hours in normal control subjects as blood pressure began to decrease. Significant negative correlations between systolic blood pressure and pulse rate occurred at 2 and 3 hours, suggesting that the early cardiovascular response to amphetamine is an increase in blood pressure that recruits reflex control of heart rate. Eighteen of these subjects had hypertensive responses. Six subjects received 5 mg haloperidol intramuscularly, and 12 others had their blood pressure monitored until normalization. Haloperidol led to a more rapid decline of some but not all indices of blood pressure, suggesting that amphetamine-induced hypertension may have a dopaminergic component.     

The hyperactive child syndrome: Peripheral sympathetic nervous system function and the effect of d-amphetamine

We evaluated sympathetic nervous system function in medication-free hyperactive children by measuring plasma levels of norepinephrine (NE) and dopamine-β-hydroxylase and then comparing the effects of two therapeutic doses of d-amphetamine to placebo in these patients. The medication-free hyperactive patients and controls had similar plasma NE levels and blood pressures while recumbent, and similar increase in NE on standing, but the patients had a larger pressor response on standing. In the hyperactive patients d-amphetamine significantly increased blood pressure, pulse rate, and NE levels. The change in NE levels correlated with the change in amphetamine levels. The medication-free patients, when more anxious, had higher plasma NE levels.     

Lithium: effects of short-term and chronic treatments in rats on the activity of dopamine-beta-hydroxylase (DBH) in the central versus peripheral nervous system

The therapeutic usefulness of lithium in mania is now well-established. However, the precise neurochemical mechanisms by which lithium brings about its effects remain poorly understood. This report describes the effects of lithium on the central and peripheral levels of activity of dopamine-β-hydroxylase (DBH), the enzyme that catalyzes the final step in the biosynthetic pathway to the formation of norepinephrine (NE) from dopamine. Since the neurotransmitter NE has been implicated in the mediation of lithium's action, what effects lithium may have on the activity of DBH was deemed worth investigating. Lithium chloride was administered intraperitoneally in rats on a short-term and chronic basis and the effects on DBH activities in the hypothalamus and serum were evaluated. A significant reduction in DBH activity occurred in the hypothalamus after short-term lithium butthere was no change following chronic treatment. In contrast, serum DBH activity remained unchanged after both acute and chronic lithium injection. Since increased noradrenergic activity in the brain has been implicated in the etiology of mania, the lithium-induced decrease in hypothalamic DBH is suggestive of a neurochemical mechanism by which lithium may act in psychotic patients.     

Locus coeruleus norepinephrine-containing neurons: effects produced by acute and subchronic treatment with antipsychotic drugs and amphetamine

Extracellular single-unit recording techniques were used to determine whether chronic treatment with either a typical antipsychotic drug (APD), haloperidol (HAL) or an atypical APD clozapine (CLOZ) causes a time-dependent reduction of spontaneously active norepinephrine (NE) neurons in the locus coeruleus (LC). Neither HAL nor CLOZ, after prolonged treatment, reduced NE activity. In addition, subchronic amphetamine (AMP) treatment did not increase NE activity. If these results can be extended to humans, they suggest that NE hyperactivity is not the cause for schizophrenic symptoms. Interestingly, chronic CLOZ markedy increased NE activity which may contribute to its low potential for causing extrapyramidal side-effects.     

Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects

Basal serum amino acids (including central monoamine precursors), central monoamines, and hormones were studied in schizophrenic patients (drug-naive; n = 20; drug-withdrawn for 3 or more days, n = 67; neuroleptic-treated, n = 23) and healthy subjects (n = 90) to answer the following questions: (1) Do neuroleptic-withdrawn and neuroleptic-naive patients differ on these serum measures? (2) What are the effects of neuroleptic treatment on these measures? (3) On which variables do drug-free and neuroleptic-treated patients differ? Because serum amino acid, central monoamine, and hormone levels were similar in drug-naive and drug-withdrawn patients, data from these groups ("drug-free") were combined and compared to those of healthy subjects and neuroleptic-treated patients. Asparagine, citrulline, phenylalanine, and cysteine were higher, while tyrosine, tryptophan, and the ratio of tryptophan to competing amino acids were significantly lower in drug-free schizophrenic patients than in healthy subjects. Dopamine was increased, and melatonin and thyroid hormones were decreased in drug-free schizophrenic patients compared to healthy subjects. Norepinephrine, epinephrine, and prolactin were higher in neuroleptic-treated men compared to drug-free male patients or healthy men. These results are consistent with the hypothesis of dopaminergic overactivity in schizophrenia, which might be caused by altered amino acid precursor availability and could be related to the decrease in melatonin and reduction in thyroid hormone levels.     

Situational panic attacks. Behavioral, physiologic, and biochemical characterization

To investigate the pathophysiology of nonpharmacologically induced panic attacks, 18 drug-free agoraphobic patients and 13 matched healthy subjects underwent structured exposure to phobic situations. Heart rate, blood pressure, and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG), cortisol, growth hormone, and prolactin levels were measured before, during, and after exposure. Fifteen patients experienced situational panic attacks during exposure. Panicking patients displayed significantly greater increases in heart rate but not blood pressure or plasma free MHPG or cortisol in comparison with the healthy subjects. Growth hormone and prolactin responses tended to be smaller in the patients. If brain noradrenergic hyperactivity occurs during situational panic attacks, it may be too brief or too restricted in regional localization to affect MHPG levels in plasma. Chronically recurrent attacks may cause an adaptation of neuroendocrine mechanisms activated by anxiety or stress.     

Evaluation of the sympathetic nervous system in trisomy-21 (Down's syndrome).

Dopamine-β-hydroxylase (DBH) is the enzyme which converts dopamine to norepinephrine (NE) and plasma DBH activity is diminished in patients with Down's syndrome. We have investigated sympathetic, noradrenergic neurotransmission in Down's patients by measuring plasma levels of NE and DBH in patients with trisomy-21 and their parents and comparing them to healthy volunteers of similar age. The Down's patients, like normal control subjects, responded to the stress of venipuncture and to standing with a significant increase in plasma levels of NE, indicating intact sympathetic nervous system responsivity. In fact the patients had significantly (p < 0·05) higher circulating levels of NE while supine and standing. Despite the higher NE levels systolic blood pressure was significantly lower in the patients (p = 0·005). Plasma DBH activity was significantly (p < 0·005) diminished in the Down's patients when compared to their parents, to age-matched controls or adult controls. While DBH does not appear to be an index of deficient sympathetic nervous activity in Down's syndrome, it may reflect the chromosome abnormality. Despite low levels of DBH, the synthetic enzyme for NE, Down's patients have normal or increased levels of NE.     

Are gender differences genetically related to catecholamine metabolism in schizophrenia?

Serum homovanillic acid (HVA) and norepinephrine (NE), serum dopamine-β-hydroxylase (DBH), platelet monoamine oxidase (MAO), and erythrocyte catechol-O-methyltransferase (COMT) have been measured in 86 healthy parents of schizophrenic patients and 36 normal control subjects. The t-test showed that serum HVA concentration was significantly higher in mothers of female patients than in mothers of male patients (p < .05); Kruskal-Wallis analysis revealed a significant difference in erythrocyte COMT activity among the mothers of male patients, mothers of female patients and female control subjects (H = 8.7, df = 2, p < .02); and the Mann-Whitney test demonstrated that erythrocyte COMT activity was significantly increased in mothers of male patients as compared with female control subjects (p < .01), but there were no significant differences in the HVA concentration and COMT activity between the fathers of male and female patients, and male control subjects. There were no significant changes in serum NE concentration, serum DBH and platelet MAO activity in these subjects. The present study suggests that catecholamine metabolism in mothers of schizophrenic patients may play a genetic role in the gender differences of schizophrenia.     

Early pharmacokinetics and clinical effects of oral D-amphetamine in normal subjects

Seven normal subjects received 0.25 mg/kg D-amphetamine orally, both after an overnight fast and again after a standard breakfast. Plasma levels, subjective and cardiovascular effects, and observer-rated activation were assessed hourly for 5 hr. Food did not affect amphetamine levels. Plasma levels peaked at 2-3 hr. Maximum cardiovascular effects generally occurred at 1 hr, whereas maximum behavioral and subjective effects occurred at 2 hr. Subjective and behavioral effects declined thereafter, in spite of substantial amphetamine levels. A separate group of 8 subjects received 0.5 mg/kg D-amphetamine orally. Plasma levels, subjective and cardiovascular effects, and activation ratings were assessed hourly for 4 hr. Maximum plasma levels were approximately twice those seen in the first group. In this case, plasma levels peaked at 3-4 hr; blood pressure and subjective and behavioral effects were all maximal at 2-3 hr and were declining by 4 hr, in spite of stable or rising plasma levels.     

Blood protein fraction comparisons of normal and schizophrenic patients.

Whole blood, plasma, or serum levels of various components were measured in fasting, drug-free control subjects and drug-free schizophrenic patients. Compared to normal controls, chronic schizophrenic patients showed increased alpha2-globulins and decreased plasma cholinesterase activity and ceruloplasmin activity, and acute schizophrenic patients showed decreased alpha2-globulins. Compared to chronic patients, acute schizophrenics showed decreased alpha2-globulins and IgA. Compared to normal controls of similar age, chronic schizophrenic patients weighed less, were shorter, and had smaller body surface area. The acute schizophrenic patients were significantly younger than the normal subjects or chronic schizophrenics but there was no difference in the other physical measurements. The present study indicates no gross disturbances in the blood variables studied. That some differences are statistically significant from controls is of scientific interest, but of no clinical value in the diagnosis of schizophrenia.     

alpha-Adrenergic receptor function in schizophrenia. Receptor number, cyclic adenosine monophosphate production, adenylate cyclase activity, and effect of drugs

alpha-Adrenergic receptor function was assessed in platelets from drug-free schizophrenic patients and control subjects. The number of alpha-receptors was similar in platelet membranes from schizophrenic patients and control subjects. In intact platelets from schizophrenic male, but not female, patients, prostaglandin E1 (PGE1)-stimulated cyclic adenosine monophosphate (cAMP) level was less than in control subjects. This defect may be due, at least in part, to decreased adenylate cyclase activity. In platelet lysates from schizophrenic patients, but not from normal control subjects, adenylate cyclase activity was diminished and PGE1-stimulated adenylate cyclase activity could be restored partially by the addition of guanosine triphosphate. Treatment with neuroleptic drugs or lithium carbonate did not change alpha-receptor number or cAMP production in platelets from schizophrenic patients, but high doses of propranolol hydrochloride increased cAMP production without affecting the number of alpha-receptors. If the production of cAMP in neurons is similar to that in platelets, diminished cAMP production may be associated with a vulnerability to schizophrenia.     

Variable attenuation of amphetamine effects by lithium.

In an open study of 8 subjects, approximately half showed some attenuation of CNS stimulant effects of amphetamine after pretreatment with lithium. Two showed specific blockade of euphoria, with persistence of some CNS stimulant effects. In 3 subjects lithium did not appear to affect the response to amphetamine. Lithium caused significant attenuation of the amphetamine-induced increase in systolic blood pressure for the group as a whole.     

Noradrenergic function in schizophrenia

Yohimbine, an alpha 2-adrenergic receptor antagonist that increases noradrenergic function, was administered to 16 healthy subjects and 18 drug-free schizophrenic patients with (n = 10) and without (n = 8) tardive dyskinesia (TD). Outcome measures of this double-blind, placebo-controlled study included changes in behavior, plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) level, blood pressure, and heart rate. A subgroup of six patients experienced a notable dysphoric arousal reaction that occurred 60 to 90 minutes following administration of 20 mg of yohimbine, this reaction was not observed in healthy subjects. The schizophrenic group as a whole (not the subgroup) showed a statistical trend toward a greater yohimbine-induced increase in plasma MHPG level and systolic sitting blood pressure. The patients with TD did not differ from those without TD or from healthy controls in their response to yohimbine. These results do not support the hypothesis that noradrenergic dysfunction plays a strong central role in the pathogenesis of schizophrenia or TD. However, further studies of noradrenergic dysfunction in sub-groups of patients with schizophrenia are indicated.     

Impaired presynaptic regulation of norepinephrine in schizophrenia. Effects of clonidine in schizophrenic patients and normal controls

Recent studies have found elevated levels of norepinephrine (NE) in CSF and brain specimens from schizophrenic patients. Presynaptic inhibitory alpha 2-adrenergic receptors regulate NE release in the brain. The hypothesis that the functional sensitivity of this presynaptic regulation of NE is impaired in schizophrenia was tested by evaluating, in schizophrenic patients and age-matched normal controls, the ability of clonidine, an alpha 2 agonist, to lower plasma levels of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and to lower blood pressure (BP). Clonidine produced a significant decrease in plasma MHPG levels in the normal control group, but did not lower plasma MHPG levels in the schizophrenic patients. Clonidine decreased BP equally in both groups. These results suggest that there is a functional subsensitivity of the inhibitory presynaptic alpha 2-adrenergic receptor in schizophrenia, which may relate to an impaired regulation of NE turnover.     

Effects of S-adenosyl-methionine on plasma norepinephrine, blood pressure, and heart rate in healthy volunteers

S-adenosyl-methionine (SAMe) is currently undergoing trials as a possible antidepressant. Because SAMe's mechanism of action is obscure and norepinephrine (NE) is often implicated in affective disorders, we studied the effects of SAMe on this neurotransmitter in volunteers. Plasma NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the supine and standing position were studied before and after acute placebo or a single 400 mg dose of SAMe and following seven daily administrations; concomitant measures were heart rate (HR) and blood pressure. Subjects were unable to distinguish acute drug from placebo, and although chronic SAMe administration was open, they reported no behavioral effects. Standing HR and plasma NE were reduced following chronic SAMe. Qualitatively similar changes are obtained following chronic treatment with monoamine oxidase inhibitors (MAOIs). However, unlike MAOIs, chronic SAMe treatment was not associated with changes in plasma MHPG. Exaggerated standing NE is found in depressed patients; SAMe may reduce this abnormal response, providing a clue for its mechanism of action in depression.     

Prolactin bioassay in schizophrenia before and after neuroleptics.

Fifteen drug-free schizophrenic male inpatients and 14 normal control subjects were studied. The schizophrenic subjects had a significantly lower ratio of bioassay prolactin to radioimmunoassay prolactin before neuroleptic treatment than they did after treatment. The ratio was lower in the drug-free patients as compared with normal controls. These findings suggest that neuroleptic medications may alter the molecular forms of serum prolactin. The results also suggest that drug-free schizophrenic patients may have a different pattern of prolactin variants than normal subjects and that this difference could be secondary to a disordered tuberoinfundibular dopamine system or long-term effects of neuroleptic drugs.     

Platelet alpha 2-adrenergic receptor function in psychiatric disorders

The inhibitory effects of norepinephrine (NE) on the cyclic adenosine-3',5'-monophosphate (cAMP) response to prostaglandin E1 (PGE1), a measure of alpha 2-adrenergic receptor function, have been compared in platelets from drug-free schizophrenic patients, depressive patients, and normal controls. The absolute value of the inhibition by NE of the cAMP response to PGE1 was smaller in platelets from schizophrenic and depressive patients than in controls. However, this result was secondary to the smaller baseline platelet cAMP response to PGE1 in patients with these disorders. Effects of NE on cAMP production did not discriminate between actively ill and remitted patients with either schizophrenia or depression. Platelet alpha 2-receptor sensitivity, as measured by the effects of NE on cAMP production, does not appear to be altered in these psychiatric disorders.     

Behavioral and biochemical effects of methylphenidate in schizophrenic and nonschizophrenic patients.

The authors examined the specific behavioral and biochemical effects of intravenous methylphenidate in a sample of schizophrenic and nonschizophrenic patients. Twenty drug-free patients participated in a double-blind, placebo randomized study of methylphenidate, with multiple samples of plasma homovanillic acid (HVA) and serum growth hormone (GH) obtained during the infusion procedure. Methylphenidate caused a significant increase in positive symptoms that was relatively specific to the schizophrenic patients and was evident even in those with otherwise dormant symptomatology. When behavioral response was correlated with the biochemical responses (i.e., changes in plasma HVA and GH), there was a significant positive relationship between the increase in the BPRS-positive symptoms as well as the hostility/suspiciousness factor, and the increase in GH. These results suggest that the expression of psychotic symptoms may be associated with increased dopaminergic postsynaptic sensitivity, although the nonspecific nature of methylphenidate's actions discourages a stronger interpretation of the results.     

Lithium distribution in mania: single-dose pharmacokinetics and sympathoadrenal function

We examined lithium distribution after a single dose of 25 mEq in 14 drug-free manic patients. Lithium concentrations were measured in plasma, red blood cells, and urine. Maximum concentrations of lithium, times at which they were attained, and influx and efflux rate constants for extracellular fluid, red blood cell, and muscle-like compartments were estimated using a three-compartment pharmacokinetic model. Tissue lithium concentrations may continue to increase for hours after plasma lithium concentrations have peaked. Rate constants for absorption, excretion, and influx and efflux for the tissue compartments were similar to those previously reported for normal subjects. Rate constants for transport into and out of the tissue compartments correlated negatively with norepinephrine or epinephrine excretion and positively with the plasma/red cell Na+ gradient. Rate constants for efflux from red blood cell and muscle compartments correlated with measures of adrenocortical function and were higher in dexamethasone nonsuppressors than in suppressors. These data show that distribution of lithium may be related to sympathodrenal activity and Na+ distribution in manic patients.     

Substance induced plasticity in noradrenergic innervation of the paraventricular hypothalamic nucleus

Single administration of the cytokine interleukin-1 alpha (IL-1), or the psychostimulant amphetamine, enhanced adrenocorticotropin hormone and corticosterone responses to a stress challenge weeks later. This long-lasting hypothalamic-pituitary-adrenal (HPA)-sensitization is paralleled by an increase in electrically evoked release of noradrenaline in the paraventricular hypothalamic nucleus (PVN). We hypothesized that these functional changes may be associated with morphological plasticity of noradrenergic projections to the PVN, a parameter that shows high reproducibility. Specific alterations in relative (nor)adrenergic innervation density were studied by using dopamine-alpha-hydroxylase (DBH) as a marker. An image analysis system was used to detect changes in the relative DBH innervation density of the PVN. Groups of adult male rats were given IL-1 (10 microg/kg i.p.), amphetamine (5 mg/kg i.p.), or saline. Three weeks later, IL-1 and amphetamine primed rats showed enhanced adrenocorticotropin hormone and corticosterone responses to an amphetamine challenge. In another set of experiments, the relative DBH innervation density was measured in different PVN subnuclei at four rostro-caudal levels. Single administration of either IL-1 or amphetamine causes three weeks later a selective decrease in relative DBH innervation density in those subnuclei of the PVN that contain high numbers of corticotrophin-releasing hormone (CRH) producing neurons: the dorsal parvocellular and medial parvocellular PVN. We conclude that (1) long-lasting sensitization induced by single exposure to IL-1 and amphetamine induces specific pattern of neuroplastic changes in (nor)adrenergic innervation in the PVN and (2) reduction of relative DBH innervation density in CRH-rich areas is associated with paradoxical increase of electrically evoked release of (nor)adrenaline.