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Validity of urinary monoamine assay sales under the “spot baseline urinary neurotransmitter testing marketing model”

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... In the endogenous state, where no or insufficient serotonin or dopamine precursors are ingested, competitive inhibition does not exist. [5][6][7][8][9][10][11][49][50][51][52][53][54][55][56] synthesis Aromatic-L-amino acid decarboxylase (AADC) metabolizes L-dopa to dopamine, 5-HTP to serotonin, histidine to histamine, and phenylalanine to phenylethylamine. Competitive inhibition may exist between the four precursors for metabolism by AADC. ...
... Administering L-dopa without balanced serotonin precursor concentrations may decrease AADC serotonin synthesis. This causes a L-dopa-induced serotonin precursor RND, Figure 2. [5][6][7][8][9][10][11][49][50][51][52][53][54][55][56] Transport Organic Cation Transporters (OCT) transport the centrally acting monoamines (serotonin, dopamine, norepinephrine, and epinephrine) and their precursors bidirectionally across cell membranes. OCT transports precursors into the cellular structures where AADC metabolism occurs. ...
... Subsequent serotonin depletion represents a serotonin precursor RND. [5][6][7][8][9][10][11][49][50][51][52][53][54][55][56] ...
... Proper OCT assay requires that initially the serotonin and dopamine systems are placed in the competitive inhibition state simultaneously, while administering adequate amounts of serotonin and dopamine amino acid precursors. The assay results are then compared in order to determine the change in urinary serotonin and dopamine concentrations associated with changes in amino acid precursor dosing values.2,3,5,6,11 ...
... The functional status of these organic cation transporters determines intracellular and extracellular (including synaptic) concentrations of these monoamines. Furthermore, it was concluded that it is virtually impossible to distinguish, via laboratory assay interpretation, individuals with or without disease or regulatory dysfunctions, even those dysfunctions that were traditionally assumed to be associated with low levels of synaptic, centrally acting monoamine levels.4,6,10 ...
... There is no objective method that identifies individuals with low concentrations of transporter-dependent monoamine concentrations in the endogenous state.13 Transporter- associated concentration trends in groups of subjects have been identified, but the day-to-day variability of monoamine concentrations in each individual comprising the group reveals that it is not possible to identify individuals with electrical dysfunction on laboratory testing and/or transporter analysis who are suffering from low levels of monoamines relative to the normal reference range.4,6,11 Diets devoid of critical amino acids will induce an AND with associated disease symptoms, but diets such as this are not the normal endogenous state of humans who develop monoamine or regulatory dysfunction-related symptoms.15,16 ...
... The DBS laboratory is accredited as a high complexity laboratory by Clinical Laboratory Improvement Amendments. OCT assay interpretation was performed by one of the authors (Marty Hinz).3–8,10–14 ...
... Proper OCT interpretation requires obtaining two or more urinary monoamine assays while taking significant amounts of varied precursor dosing values consistently for 5 days minimum to achieve equilibrium. Serial assays are then compared to determine the impact of precursor dosing value changes.3–8,10–14 ...
... This causes less serotonin and dopamine to show up in the final urine as waste. The general direction of urinary serotonin levels in transport and final urinary levels can be predicted in the competitive inhibition state; the exact amount of movement secondary to amino acid precursor changes, however, is individualized.3–8,10–14 ...
... When competitive inhibition under this system exists, changes to either serotonin or dopamine concentrations individually will affect both serotonin and dopamine concentrations in a predictable manner. 1,[7][8][9][10][11][12][13][14][15][16] Relative nutritional deficiency A relative nutritional deficiency (RND) exists when optimal nutrient intake cannot meet system needs. Parkinson's disease may induce many RNDs associated with depletions of serotonin, dopamine, norepinephrine, epinephrine, thiols (homocysteine, l-methionine, S-adenosyl-l-methionine, S-adenosyl-homocysteine, cystathione, l-cysteine, and glutathione), l-tyrosine, and l-tryptophan. ...
... If dopamine depletion is induced, 5-HTP is no longer functioning as a nutrient; it is a drug. 1,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] When l-dopa is administered as a single agent, it may deplete serotonin, and would then be considered a drug, not a nutrient. 1,7,[30][31][32][33][34] ...
... To understand the discussions contained herein, the concepts of the endogenous state and competitive inhibition state need to be defined. 1,[12][13][14][15][16][17][18][19][20] Humans taking no supplemental serotonin or dopamine amino acid precursors are in the endogenous state. The endogenous state also exists when L-dopa or 5-HTP ...
... These were patients who had collected urine samples in the competitive inhibition state and then submitted them for serotonin and dopamine assay followed by OCT2 functional status determination. 1,2,[13][14][15][16][17][18][19][20] The Parkinson's disease patients' diagnostic evaluations were performed under the care of a licensed medical doctor or doctor of osteopathic medicine and then entered as a working diagnosis on submission of laboratory samples. The diagnosis of Parkinson's disease was then added to the database without further diagnostic verification. ...
... Subjects in the endogenous state, with and without monoamine-related disease, if not suffering from a monoamine- secreting tumor, cannot be differentiated by laboratory monoamine assays including MTO. Statistical distribution of monoamine levels are the same in subjects with and without disease.1,5,7,11 ...
... This did not work because it did not take into account the effects of transporters. This high/low approach to assay interpretation, as a guide to amino acid dosing values, was no more effective than simply giving amino acid precursors randomly.5,7,11 ...
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Two primary categories of nutritional deficiency exist. An absolute nutritional deficiency occurs when nutrient intake is not sufficient to meet the normal needs of the system, and a relative nutritional deficiency exists when nutrient intake and systemic levels of nutrients are normal, while a change occurs in the system that induces a nutrient intake requirement that cannot be supplied from diet alone. The purpose of this paper is to demonstrate that the primary component of chronic centrally acting monoamine (serotonin, dopamine, norepinephrine, and epinephrine) disease is a relative nutritional deficiency induced by postsynaptic neuron damage. Monoamine transporter optimization results were investigated, reevaluated, and correlated with previous publications by the authors under the relative nutritional deficiency hypothesis. Most of those previous publications did not discuss the concept of a relative nutritional deficiency. It is the purpose of this paper to redefine the etiology expressed in these previous writings into the realm of relative nutritional deficiency, as demonstrated by monoamine transporter optimization. The novel and broad range of amino acid precursor dosing values required to address centrally acting monoamine relative nutritional deficiency properly is also discussed. Four primary etiologies are described for postsynaptic neuron damage leading to a centrally acting monoamine relative nutritional deficiency, all of which require monoamine transporter optimization to define the proper amino acid dosing values of serotonin and dopamine precursors. Humans suffering from chronic centrally acting monoamine-related disease are not suffering from a drug deficiency; they are suffering from a relative nutritional deficiency involving serotonin and dopamine amino acid precursors. Whenever low or inadequate levels of monoamine neurotransmitters exist, a relative nutritional deficiency is present. These precursors must be administered simultaneously under the guidance of monoamine transporter optimization in order to achieve optimal relative nutritional deficiency management. Improper administration of these precursors can exacerbate and/or facilitate new onset of centrally acting monoamine-related relative nutritional deficiencies.
... Administration of supplemental L-tyrosine with phenelzine writing no concerns have been raised regarding concomitant administration of L-tyrosine with phenelzine. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] The primary cause of phenelzineassociated hypertensive crisis ...
... were associated with greater sleep disturbance. to acknowledge our use of urinary dopamine as a proxy measure may limit the inferences we can make about the associations between CNS dopamine, sleep, and immune status (Hinz et al., 2011). In addition, we were limited in that we had access to only one immune measure (CD4 count) and one dopamine measure. ...
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Sleep disturbance is associated with dopamine dysregulation, which can negatively impact immune status. Individuals living with HIV experience more sleep difficulties, and poor sleep may compound immune decrements associated with HIV infection. Little research has examined associations between sleep, dopamine, and immune status (CD4 count) in individuals with HIV. As ethnic minority women living with HIV (WLWH) are at heightened risk for HIV disease progression, we related sleep reports to both CD4 count and dopamine levels in a cohort of ethnic minority WLWH. Participants were 139 low-income WLWH (ages 20-62; 78.3% African-American or Caribbean) who reported both overall sleep quality and sleep disturbance on the Pittsburgh sleep quality index (PSQI). CD4 count and HIV viral load were measured via morning peripheral venous blood samples, and concentrations of dopamine were measured via 24-h urine collection. Covariates included HIV viral load, length of time since HIV diagnosis, HAART adherence, perceived stress and depression. After controlling for all covariates, greater sleep disturbance was associated with significantly lower CD4 count (β=-.20, p=.03) and lower levels of dopamine (β=-.25, p=.04). Poorer overall sleep quality was marginally associated with lower CD4 count (β=-.16, p=.08), and was not associated with dopamine. Our analyses suggest that sleep disturbance is independently related with immune status and dopamine levels in WLWH. Lower levels of dopamine may indicate neuroendocrine dysregulation and may impact immune and health status. Results highlight sleep disturbance rather than overall sleep quality as potentially salient to neuroendocrine and immune status in ethnic minority WLWH.
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Physiological and pharmacological evidence makes it clear that brain monoamines are involved in the regulation of the secretion of all six established anterior pituitary hormones: adrenocorticotropin (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin. Aminergic control of pituitary secretion has been a popular topic for reviews and many have appeared covering both the general topic and specialized aspects. This review focuses primarily on papers published in the last 2 years, with most of the references to the older literature via reviews; for the most part only papers published or otherwise available before January 1978 are included.
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Basic research in autism is reviewed. There is mounting indication, but as yet inconclusive evidence, of unique physiologic disturbances etiologically related to autism. Additionally there is indication that some of the physiologic disturbances found in autistic children are also present in children with other developmental disorders. Children called autistic probably represent a complex of clinically similar manifestations in a variety of different subgroups of children, each subgroup representing a basically different physiologic disturbance. However, the possibility remains that there is only one basic disturbance that in varying degrees affects many body systems and thus manifests in a variety of overlapping syndromes. Objective markers are needed so as to allow the demarcation of subgroups of autistic children for further study. Possible markers may be decreased duration of postrotatory nystagmus, auditory evoked response deviations, lymphocytic hyporesponsivity, increased blood platelet serotonin efflux, and/or the presence of urinary DMT or bufotenin.
Article
Various organic and psychosomatic factors have been postulated over the years as etiologic events antedating the onset of Graves' disease. In some patients psychological events have appeared to be important in the evocation of symptoms. Although examples of the latter have been described in adults for many years, there is little published on this phenomenon in children. The present study delineates findings in two boys and two girls with an age range of 8 to 14 years. Separating experiences appeared to be related to the onset or relapse of Graves' disease in these particular cases. In three of the patients the trigger event was represented by bereavement after death of a close relative; in the fourth case the boy's loss was enforced and traumatic separation from his mother figure. In all these children depression was the common response to loss. The observed relationship between the affective disturbance and Graves' disease is compatible with one or more hypothetical models. One such pathway, via depletion of brain monoamines associated with the state of depression, could cause an activation of the hypothalamic-pituitary-adrenal axis with resultant suppression of immune surveillance. This could permit the formation of thyroid-stimulating immunoglobulins (TSI) and hence Graves' disease in genetically susceptible (HLA B-8) persons.
Article
Using a sensitive and precise radioimmunoassay for human TSH we have demonstrated significant elevations in serum TSH levels in euthyroid volunteers following administration of the dopamine receptor blocking drug metoclopramide when compared with placebo. The degree of TSH response is significantly greater in females than in males and is sustained over a 3-hour period after a single oral 10 mg dose of metoclopramide. The degree of TSH release after metoclopramide is inversely related to the basal TSH level suggesting that dopamine is a determinant of low daytime TSH levels and is thus implicated in the circadian rhythm of TSH secretion. Pretreatment with 10 mg of metoclopramide orally, one hour before TRH administration leads to significant enhancement of the TSH response to TRH. Our findings provide further evidence for the physiological inhibitory role of dopamine in the contol of TSH secretion in normal man. The possible mode of action of dopamine and the clinical implications of this neuroregulatory pathway are discussed.
Article
To examine whether the concentration of NE in human plasma is dependent on the vascular source of the sample and to examine the contribution of the kidney to urinary NE, 14 normal men were studied. Plasma samples were obtained from a superficial forearm vein, and radial artery and urine samples were obtained during 1 hr of recumbency and 1 hr of upright posture. The Vne was greater than Ane during both recumbency and upright posture in black males. Such differences were not seen in age-matched white subjects. Stimulation of the sympathetic nervous system by upright posture increased both Vne and Ane in all subjects. NE concentrations in simultaneously obtained arterial and venous samples were different during the time of cardiovascular adjustments to upright posture. The urinary Xne increased after standing. Endogenous CCr decreased, whereas apparent NE clearance, calculated from the Ane, increased after standing, suggesting that a major portion of the augmented urinary Xne induced by upright posture was from an intrarenal source. We conclude that the concentration of NE in human blood is related to the specific vascular bed from which the sample is obtained, and that urinary NE is not solely derived from plasma by glomerular filtration but also arises from an unidentified renal source.
Article
Metergoline (4 mg) and methysergide (3 mg), two serotonin antagonists known to inhibit prolactin secretion in normal subjects, and the dopaminergic agonist, bromocriptine (2.5 mg) were orally administered in hyperprolactinemic patients. Mean serum prolactin concentration was significantly decreased between 120 and 240 min following the ingestion of all three drugs in comparison with a placebo; a consistent reduction to below 50% of basal values occurred in 10 of 14 patients after metergoline, in 5 of 10 after methysergide, and in 11 of 14 after bromocriptine administration. These data indicate that serotonin antagonists may acutely lower serum prolactin levels in hyperprolactinemic patients similarly to bromocriptine, though their mechanism of action is most likely different.
Article
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 function.
Article
In ten normal subjects and in twenty acromegalic patients plasma levels of growth hormone were studied after administration of L-dopa and a dopamine infusion. In the ten normal subjects L-dopa, but not dopamine, increased plasma levels of GH. In the acromegalic patients both L-dopa and dopamine were followed by an inhibition of GH release. Since dopamine does not cross the blood-brain barrier, these results, although not excluding a site of action at median eminence level, support the thesis that the inhibitory effect of dopaminergic stimulation on GH release in acromegaly possibly involves receptors present on GH-secreting cells.
Article
Results of evaluations of adrenal function in 11 patients with carcinoid tumors are presented. Nine patients had tumors that made and secreted serotonin resulting in elevated 5-hydroxyindoleacetic acid (5-HIAA), elevated serum serotonin, and the carcinoid syndrome; while two patients had tumors that did not make serotonin and that did not cause elevated 5-HIAA excretion or elevated serum serotonin. All of the patients had normal 24-hr 17-hydroxycorticosteroid excretion. In the group of patients with tumors actively secreting serotonin, the correlation between 17-hydroxycorticosteroid and 5-HIAA excretion (r = 0.44) was not significant. Six of these patients pretreated with cyproheptadine (CYPRO), a serotonin antagonist, experienced a 36% mean decrease in 17-hydroxycorticosteroid excretion, a finding that was not present when three of them were treated with triprolidine (TPRO), an antihistamine.
Article
The central adrenergic innervation of the cerebral microvessels may play a role in the control of blood-brain barrier permeability. To pursue the study of this hypothesis we investigated the effect of noradrenaline on both the permeability of the blood-brain barrier to sodium fluorescein and on the pinocytotic activity of cerebral endothelial cells in the rat. Noradrenaline, stereotactically injected in the right lateral cerebral ventricle, significantly increased the cerebral extraction ratio of sodium fluorescein in a dose-dependent way. The same effect was induced by phenylephrine. Prostaglandin F2α had no significant effect on the passage of sodium fluorescein through the blood-brain barrier. The effect of noradrenaline (150 µg) on the cerebral extraction ratio of sodium fluorescein was totally blocked by phenoxybenzamine (25 mg/kg i.p., 24 h before noradrenaline). Noradrenaline (150 µg) significantly increased the pinocytotic activity of cerebral endothelial cells. Phenoxybenzamine (as above) reduced the effect of noradrenaline on pinocytosis. It is concluded that noradrenaline increases the blood-brain barrier's permeability to sodium fluorescein, most probably through an effect on alpha adrenoceptors. The increase induced in the blood-brain barrier's permeability by noradrenaline seems to be due, at least in part, to an increase in the pinocytotic activity of endothelial cells.
Article
1. In decerebrated rabbits, repetitive stimulation of the high-threshold afferents of the left common peroneal (CP) nerve evokes prolonged depression of the sural-gastrocnemius medialis (GM) reflex recorded in the same limb. This inhibition is antagonized by co-administration of the opioid antagonist naloxone with the alpha 2-adrenoceptor antagonist idazoxan. The present study was designed to investigate whether such inhibition could be elicited from the contralateral hindlimb or the forelimbs. 2. The sural-GM reflex of decerebrated rabbits was depressed for more than 15 min after stimulation of either ipsilateral or contralateral common peroneal (CP) or median nerves with 500 pulses of 20 V, 1 ms given at 5 Hz. The order of efficacy for generating this inhibition was ipsilateral CP greater than contralateral CP greater than or equal to ipsilateral median = contralateral median. In three of thirty-nine rabbits, stimulation of the median nerves caused facilitation of the sural-GM reflex. 3. Idazoxan (1-2 mg/kg I.V.) did not significantly alter the depressant effect of ipsilateral CP stimulation but reduced that evoked by either median nerve and almost abolished the inhibition evoked from the contralateral CP nerve. 4. Naloxone (0.25 mg/kg I.V.) reduced the effects of ipsilateral CP stimulation, did not alter the inhibition evoked from contralateral CP, and had equivocal actions on the responses to median nerve stimulation. 5. When given together, the two antagonists almost abolished the effects of stimulating the median nerves and the contralateral CP nerve, and markedly reduced the inhibition evoked from the ipsilateral CP nerve. 6. These data show that prolonged inhibition of the sural-GM reflex can be evoked by stimulation of nerves in all four limbs and that in each case the inhibition can be blocked or reduced by co-administration of antagonists to opioid and alpha 2-adrenergic receptors. Such persistent inhibition of reflexes may serve to inhibit withdrawal reflexes in situations where interruptions to normal movement would be disadvantageous.
Article
At first glance, it is satisfying to see the progress which has been made in the study of neurotransmitters. We have learned a great deal in the last number of years. First, we have been able to identify previously unknown compounds which affect the nervous system or associated peripheral organs. We now know a great deal about the metabolism of these molecules including their synthesis and catabolism. We have learned to identify and to classify their receptors. We have learned that alterations in the effects of neurotransmitters may be responsible for certain pathologies or may be a function of normal aging. Yet, we still have far to go in our research. There are neurotransmitters still to be discovered. We need to continue our efforts because there is still a large amount of confusion in the literature, for example, far too many contradictory reports concerning the effects of age confuse rather than clarify. Possibly order may return to the literature if investigators can agree on some basic tenets. For example, we need a basic definition of old. Some research groups consider 12-month-old rats as old while other groups consider them to be young individuals. We need to have standardization of methodology so that the conclusions can have validity. Once again certain investigators use whole brain homogenates while others use only discrete portions. We need to consider whether the effect we see in our experiment is primary or secondary to aging. We can be certain that due to the aging population, the importance of basic research of age-dependent changes in neurotransmitters and neuroreceptors will increase in the future.
Article
Fluoxetine is a highly specific serotonin reuptake inhibitor. In studies that used a dose of 60 mg once daily, fluoxetine-treated patients consistently had greater weight loss than placebo-treated patients. In six double-blind, placebo-controlled studies of 6-8 wk duration, mean weight changes on fluoxetine were approximately 0.5 kg/wk. Longer term studies have shown maximum mean weight loss to occur at 12-20 wk of therapy. Studies have consistently shown improvements in indices of glycemic control as well as weight loss in obese diabetic patients. Safety analysis has been performed on data from 3491 obese patients in controlled clinical trials of up to 52 wk duration. Adverse events with an incidence of greater than 5%, which were reported significantly more frequently by fluoxetine-treated patients, were headache, asthenia, nausea, diarrhea, somnolence, insomnia, nervousness, sweating, and tremor. Fluoxetine is effective, well tolerated, and safe in the treatment of obesity and obese diabetics.
Article
To study the role of serotonin in gastrointestinal function in mice, a peripheral deficiency was induced by administration of 2,4-diamino-6-hydroxypyrimidine, an inhibitor of tetrahydrobiopterin (6-[dihydroxypropyl-(L-erthro)-5,6,7,8,-tetrahydropterin) (BH4) biosynthesis. BH4 is an essential cofactor for tryptophan hydroxylase, the rate limiting enzyme in the biosynthesis of serotonin. When 2,4-diamino-6-hydroxypyrimidine (DAHP) was administered for 4 days at the dose of 3 g/kg/day, serotonin decreased in the duodenum and colon to approximately 46 and 40% of the control levels, respectively. These mice showed visual signs of gastrointestinal dysfunction in addition to a remarkable decrease in uptake of a p.o. glucose load. The decrease in serotonin was prevented and prevention of the apparent dysfunction of digestive tract was observed by simultaneous administration of (6R)BH4. Serotonin levels in the brain and blood were also decreased by treatment with p-chlorophenylalanine, an irreversible inhibitor of tryptophan hydroxylase. In contrast, DAHP had no effect on brain serotonin levels, presumably due to poor brain penetration. DAHP caused a rapid decrease (T1/2 of less than 12 hr) in the BH4 levels in all tissues examined, except in the brain. The BH4 level returned to within the normal range less than 24 hr after cessation of the administration of DAHP, a finding which suggests that the BH4 level is in a dynamic steady state maintained by rapid local biosynthesis. Thus, the local biosynthesis of BH4 supports normal digestive functions, presumably by controlling normal serotonin biosynthesis.
Article
Monoamine and their acid metabolites were determined in the CSF of 18 drug-treated chronic schizophrenic patients with the symptoms of tardive dyskinesia and neuroleptic-induced Parkinsonism (Parkinsonism). Six healthy volunteers were used as the control group. The norepinephrine (NE) levels were found to be significantly higher in the patients with tardive dyskinesia than in the controls. Furthermore, elevated CSF NE levels were also observed in the patients with Parkinsonism. Epinephrine (E) and Dopamine (DA) were not present in the CSF of the control group, whereas measurable levels of DA could be detected in 4 out of 9 and E was found in 8 out of 9 patients with tardive dyskinesia. The mean concentration of HVA was slightly but not significantly elevated in the patients with tardive dyskinesia and Parkinsonism. The mean values of CSF 5-HIAA were all within the normal range in both patient groups. From the above results, it was suggested that abnormal adrenergic activity rather than abnormal dopaminergic activity may play an important role as a mechanism in the etiopathogenesis of extrapyramidal disorders. Furthermore, in the patients with Parkinsonism, CSF neurochemical observations were similar to those of the patients with tardive dyskinesia in this study. It may help to explain the clinical coexistence of tardive dyskinesia and neuroleptic-induced Parkinsonism.