Plasma Monoamine Metabolite Levels Research Articles

COMT Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia.

IntroductionThe COMT Val 108/158 Met polymorphism (rs4680) may affect treatment response to antipsychotics, as well as metabolism and dynamics of neurotransmitters during the treatment of schizophrenia. We investigated the effects of the COMT Val 108/158 Met polymorphism on treatment response to aripiprazole and plasma monoamine metabolite levels in patients with acute schizophrenia.Materials and methodsForty patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured Positive and Negative Syndrome Scale (PANSS) and plasma levels of homovanillic acid (HVA) and plasma MHPG (3-methoxy-4-hydroxyphenethyleneglycol) at baseline and endpoint. The COMT Val 108/158 Met polymorphism was genotyped with the polymerase chain reaction and restriction fragment length polymorphism.ResultsThere were significant genotype–time interactions on PANSS total and general psychopathology scores, with Met/Met genotype showing greater improvement. The response rate to aripiprazole did not differ between COMT Val 108/158 Met genotype groups. We found a significant time effect on plasma MHPG levels, but no time effect on plasma HVA levels or time–genotype interactions in the plasma levels of HVA and MHPG. Although the responder rate did not differ among the 3 genotype groups.ConclusionOur results suggest that individuals with the Met/Met genotype had greater improvement in PANSS score after the treatment with aripiprazole. On the other hand, the Val 108/158 Met polymorphism may not induce changes in plasma levels of monoamine metabolites during aripiprazole treatment. Because of the small sample size, further studies are needed to confirm and to extend our results.

Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria.

Phenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis. We therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available. Mean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020). These findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

Associations between five-factor model of the Positive and Negative Syndrome Scale and plasma levels of monoamine metabolite in patients with schizophrenia

The five-factor model of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia symptoms is the most common multiple-factor model used in analyses; its use may improve evaluation of symptoms in schizophrenia patients. Plasma monoamine metabolite levels are possible indicators of clinical symptoms or response to antipsychotics in schizophrenia. We investigated the association between five-factor model components and plasma monoamine metabolites levels to explore the model's biological basis. Plasma levels of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography in 65 Japanese patients with schizophrenia. Significant negative correlation between plasma 5-HIAA levels and the depression/anxiety component was found. Furthermore, significant positive correlation was found between plasma MHPG levels and the excitement component. Plasma HVA levels were not correlated with any five-factor model component. These results suggest that the five-factor model of the PANSS may have a biological basis, and may be useful for elucidating the psychopathology of schizophrenia. Assessment using the five-factor model may enable understanding of monoaminergic dysfunction, possibly allowing more appropriate medication selection. Further studies of a larger number of first-episode schizophrenia patients are needed to confirm and extend these results.

Near-infrared spectroscopy and plasma homovanillic acid levels in bipolar disorder: a case report

Misdiagnosis of bipolar disorder is a serious, but not unusual problem for patients. Nevertheless, there are few biomarkers for distinguishing unipolar and bipolar disorder. Near-infrared spectroscopy (NIRS) is a noninvasive and useful method for the measurement of hemoglobin concentration changes in the cortical surface area, which enables the assessment of brain function. We measured NIRS and plasma monoamine metabolite levels in a patient with bipolar disorder. A 22-year-old man was admitted due to major depression. At admission, NIRS findings showed oxygenated hemoglobin reincrease in the posttask period, which is characteristic of schizophrenia. After treatment with paroxetine, he became manic with psychotic symptoms. His plasma level of homovanillic acid just before the manic switch was ten times higher than that just after paroxetine initiation. Treatment with lithium and antipsychotics was successful, and plasma homovanillic acid decreased after treatment. In this case, the NIRS findings may predict a possible risk of a manic switch, which is likely induced by paroxetine. NIRS may be able to help distinguish unipolar and bipolar disorder in clinical settings.

High plasma monoamine metabolite levels in Cotard's syndrome

Cotard's syndrome, characterized by nihilistic delusions, mostly occurs in presenile women and is accompanied by depression. The French physician Jules Cotard first presented a case of this syndrome in 1880.1 Its cause, however, still remains unclear. ‘I have no brain, heart, stomach or entrails. My body has entirely fallen into decay and only spirit exists. I can't even die and would live forever.’ These are the words of a 62-year-old woman diagnosed with Cotard's syndrome at our hospital. We consider this case significant because of the marked biochemical changes that occurred in her body, or ‘the dead body,’ according to her. The patient commenced treatment for depression in 2007, and was admitted to our hospital in April 2010 because of nihilistic delusions, appetite loss, and furious excitement. Before admission, her adherence to medication was poor, and she took only paroxetine (10 mg/day) irregularly. On admission, she had neither fever nor consciousness-related disorders. The results of various tests revealed only minor changes, for example, slight dehydration and undernourishment. No laboratory finding indicated renal failure, inflammation, or endocrine abnormality. The brain magnetic resonance imaging scan showed slight cortical atrophy compatible with her age. However, considerable changes were observed in the plasma monoamine metabolite levels on admission; the homovanillic acid (HVA, dopamine metabolite) level was 154.8 ng/mL (normal range for 50–60-year-old subjects, 4–15 ng/mL); the total 3-methoxy-4-hydroxyphenylglycol (MHPG, noradrenaline metabolite) level was 202.1 ng/mL (normal range, 16–26 ng/mL); and the free MHPG level was 57.9 ng/mL (normal range, 4–7 ng/mL). The patient was diagnosed with Cotard's syndrome that developed during the course of psychotic depression. After admission, she was treated with an antidepressant (amoxapine, 50–90 mg/day) and antipsychotics (mainly olanzapine, 2.5–10 mg/day). The varied psychotic symptoms gradually improved, and the monoamine levels returned to approximately normal. At the time of discharge in June, the patient said ‘My spirit comes back to my body.’ Recently, researchers have tried to formulate a neuropsychological theory to explain this syndrome and to identify the structural changes associated with this syndrome.2 However, these approaches have failed to adequately explain the severe and enigmatic symptoms of this syndrome, even though previous studies have demonstrated high dopaminergic activities in psychotic depression.3 In this case, we focused on the plasma monoamine metabolite levels, which had drastically increased, and then normalized, on improvement of clinical symptoms. The high levels of HVA and total and free MHPG were not thought to be due to medication before admission, taking into account that her adherence to medication was poor. In addition, laboratory findings did not suggest any physical condition that could be responsible for the increased plasma monoamine metabolite levels. We attribute the symptoms of this patient to the broad disruption of the neurotransmission systems, including the dopamine and noradrenaline systems. In conclusion, we introduce a new standpoint: some patients develop Cotard's syndrome in the presence of other neurochemical disorders.

The Role of Noradrenergic and Dopaminergic Hyperactivity in the Development of Spontaneous Recurrence of Methamphetamine Psychosis and Susceptibility to Episode Recurrence

The role of dopaminergic activity in susceptibility of methamphetamine (MAP) psychosis (flashbacks) to subsequent spontaneous recurrences was studied. Plasma monoamine metabolite levels were assayed in 23 flashbackers, of whom 10 experienced a single flashback, 8 exhibited subsequent flashbacks and 5 with the last episode; 18 nonflashbackers with a history of MAP psychosis; 9 subjects with persistent MAP psychosis; and 19 MAP user and 10 nonuser controls. All flashbackers had undergone frightening stressful experiences during previous MAP use. Their flashbacks were triggered by mild psychosocial stressors. Plasma norepinephrine (NE) levels increased with the increase in plasma levels of 3-methoxytyramine (3-MT), an index of dopamine release, during flashbacks in the 23 flashbackers. Of these, the 8 with subsequent episodes had markedly increased NE levels and increased 3-methoxytyramine levels during flashbacks. However, the 5 flashbackers with the last episode had moderately increased NE levels, and the 10 with a single episode displayed small increases in NE levels during flashbacks. Their 3-MT levels did not significantly differ from the levels in the control groups. Thus, increased DA release in addition to robust noradrenergic hyperactivity in response to mild psychosocial stressors may be important in susceptibility to subsequent flashbacks.

Factors for susceptibility to episode recurrence in spontaneous recurrence of methamphetamine psychosis.

The relation between increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic changes, and susceptibility to subsequent spontaneous recurrences of methamphetamine (MAP) psychosis (flashbacks) was examined. Plasma monoamine metabolite levels were assayed in 19 flashbackers, of whom 10 experienced a single flashback and 9 exhibited subsequent flashbacks, 18 nonflashbackers with a history of MAP psychosis, 9 subjects with persistent MAP psychosis, and 22 MAP user and 10 nonuser controls. All flashbackers had undergone frightening stressful experiences during previous MAP use. They exhibited flashbacks in response to mild psychosocial stressors. There was no significant difference in the number of stressful experiences and having mild psychosocial stressors between the two flashbacker subgroups. Plasma norepinephrine (NE) levels increased with a small increase in plasma levels of 3-methoxytyramine (3-MT), an index of dopamine release, during flashbacks in the 19 flashbackers. Of the 19 flashbackers, the 9 with subsequent episodes had markedly increased NE levels and slightly increased 3-MT levels during flashbacks, while the 10 with a single episode displayed small increases in NE and 3-MT levels during flashbacks. The 9 flashbackers with subsequent episodes had a longer duration of imprisonment than the 10 flashbackers with a single episode. Thus, robust noradrenergic hyperactivity with slightly increased DA release in response to mild stress may predict subsequent flashbacks. Long-term exposure to distressing situations appears to contribute to susceptibility to subsequent flashbacks.

Increased sensitivity to stress associated with noradrenergic hyperactivity, involving dopaminergic hyperactivity in spontaneous recurrences in methamphetamine psychosis

Abstract The study examined the significance of increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic changes in spontaneous recurrences of methamphetamine (MAP) psychosis (flashbacks). Plasma monoamine metabolite levels were assayed in the subjects: 19 flashbackers, 18 non-flashbackers with a history of MAP psychosis and 37 controls. Monoaminergic values underwent a square-root transformation. All flashbackers had been exposed to stressful events plus MAP-induced fear-related psychotic symptoms (n = 11) or fear-related symptoms alone (n = 8). Factors triggering flashbacks met the DSM-III-R criteria for mild psychosocial stressors. During flashbacks norepinephrine levels increased markedly and 3-methoxytyramine, which is indicative of dopaminergic activity, increased to a lesser extent. Among the flashbackers, 11 with a history of stressful events plus fear-related symptoms displayed further a small increase in 3-methoxytyramine levels. Thus, stressful events plus fear-related symptoms, together with MAP use, may induce noradrenergic hyperactivity and some degree of dopaminergic hyperactivity in response to mild stressors. Increased sensitivity to stress associated with a predominance of noradrenergic over dopaminergic hyperactivity may be a precipitating factor in flashbacks.

Increased sensitivity to stress in spontaneous recurrence of methamphetamine psychosis: noradrenergic hyperactivity with contribution from dopaminergic hyperactivity.

The significance of increased sensitivity to stress associated with noradrenergic hyperactivity involving dopaminergic change in spontaneous recurrences of methamphetamine (MAP) psychosis (flashbacks) was examined. Plasma monoamine metabolite levels were assayed in 18 subjects with flashbacks who had been exposed to stressful events plus MAP-induced frightening psychotic symptoms (N = 11) or frightening psychotic symptoms alone (N = 7) during previous MAP use, in 15 nonflashbackers with a history of MAP psychosis, in 8 subjects with persistent MAP psychosis, and in 27 control subjects. Monoaminergic values were subjected to a square-root transformation, rendering the distribution normal. The numbers of stressful events (mostly threatening events) and frightening psychotic symptoms were significantly higher in the flashbackers than in the nonflashbackers. Factors triggering flashbacks were mild psychosocial stressors (mostly a mild fear of other people). During flashbacks, plasma norepinephrine levels increased, and the flashbackers, 11 of whom had experienced stressful events plus frightening psychotic symptoms, had an additional small increase in plasma levels of 3-methoxytyramine, which is indicative of dopamine release. Thus, threatening stressful events, together with MAP use, may induce noradrenergic hyperreactivity to subsequent mild stressors. Threatening, stressful events plus frightening psychotic symptoms may further induce increased dopamine release in response to mild stressors. Increased sensitivity to stress associated with noradrenergic hyperactivity involving increased dopamine release may have elicited memories of MAP psychosis related to frightening, stressful experiences. The increased sensitivity may be critical for the development of flashbacks.

Stress induced spontaneous recurrence of methamphetamine psychosis: the relation between stressful experiences and sensitivity to stress

We examined increased sensitivity to stress in relation to spontaneous recurrences of methamphetamine (MAP) psychosis (i.e., flashbacks). Plasma monoamine metabolite levels were assayed in: 26 flashbackers, of whom 11 were on neuroleptics before and during the study, and the other 15 received neuroleptics in the course of the study; 18 non-flashbackers with a history of MAP psychosis; eight subjects with persistent MAP psychosis; and 23 MAP user and 11 non-user controls. The 26 flashbackers had experienced stressful events and/or MAP-induced fear-related psychotic symptoms during previous MAP use. Mild psychosocial stressors then triggered flashbacks. During flashbacks plasma norepinephrine levels increased markedly; among the flashbackers, those with a history of stressful events, whether or not they had experienced fear-related symptoms, showed a further increase in 3-methoxytyramine levels. Stressful experiences, together with MAP use, may therefore induce sensitization to stress associated with noradrenergic hyperactivity, involving increased dopamine release, and so triggering flashbacks.

Increased sensitivity to stress and episode recurrence in spontaneous recurrence of methamphetamine psychosis.

Increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic changes may precipitate stress-related psychiatric disorders. The present study examines the relation between this increased sensitivity and vulnerability to subsequent spontaneous recurrences of methamphetamine (MAP) psychosis (i.e. flashbacks). Plasma monoamine metabolite levels were assayed in 18 subjects with flashbacks, of whom ten experienced a single flashback and eight experienced further subsequent flashbacks; in 21 subjects with a history of MAP psychosis who did not experience flashbacks; and 33 controls. A square-root transformation was applied to monoaminergic values, rendering the distribution normal. The subjects with flashbacks had undergone frightening stressful experiences during previous MAP use. The dominant factor triggering flashbacks was a mild fear of other people. During flashbacks, plasma noradrenaline levels markedly increased and 3-methoxytyramine levels, an indicator of dopamine release, were elevated. Among the 18 subjects with flashbacks, the ten with subsequent flashbacks had markedly increased noradrenaline levels during flashbacks, whereas the eight with a single flashback displayed small increases in noradrenaline levels as well as 3-methoxytyramine levels. Thus, a mild fear of other people may have elicited memories of MAP psychosis, related to frightening stressful experiences through increased sensitivity to stress associated with noradrenergic hyperactivity, involving increased dopamine release. Robust noradrenergic hyperreactivity to mild stress may predispose subjects to subsequent flashbacks.

Factors affecting the development of spontaneous recurrence of methamphetamine psychosis.

The process triggering spontaneous recurrences of methamphetamine (MAP) psychosis (i.e. flashbacks) was studied in 41 flashbackers, along with 84 non-flashbackers with a history of MAP psychosis. Plasma monoamine metabolite levels were assayed in 25 of the 41 flashbackers, 16 of the 84 non-flashbackers, 9 subjects with persistent MAP psychosis and 28 control subjects. All flashbackers had experienced threatening events or frightening paranoid-hallucinatory states during previous MAP use. The dominant factor triggering flashbacks was a mild fear of other people. Plasma norepinephrine levels were elevated during flashbacks. The results suggest that a mild fear of other people may have elicited memories of MAP psychosis associated with threatening experiences through increased sensitivity to psychosocial stressors. As a result the flashbacks occurred, including an increase in peripheral noradrenergic activity.

Noradrenergic activity and spontaneous recurrence of methamphetamine psychosis

The process that triggers flashbacks due to previous methamphetamine (MAP) psychosis was studied in 28 flashbackers, along with 84 non-flashbackers with a history of MAP psychosis. We measured plasma monoamine metabolite levels in 12 of the flashbackers and eight of the non-flashbackers, along with 28 normal controls. Most flashbackers had undergone frightening experiences during previous MAP use. The dominant triggering factor was a mild fear of other people. Plasma norepinephrine (NE) levels in the 12 flashbackers were increased during flashbacks. Thus, MAP use associated with threatening experiences may have increased sensitivity to stressors, leading to the occurrence of flashbacks, including exaggerated noradrenergic activity.