Pathophysiology Of Mania Research Articles

Downregulation of microRNA-330-5p induces manic-like behaviors in REM sleep-deprived rats by enhancing tyrosine hydroxylase expression.

In our pilot study, we found an increase in tyrosine hydroxylase (Th) mRNA expression in the prefrontal cortex of 72-h REM sleep-deprived (SD) rats, a mania model. Additionally, the expression levels of miR-325-3p, miR-326-3p, and miR-330-5p, the predicted target miRNAs on TH, were significantly decreased. Based on these results, in this study, we investigated whether miRNA-325-3p, miR-326-3p, and miR-330-5p modulate TH and manic-like behaviors in SD rats. Manic-like behaviors were assessed using the open field test (OFT) and elevated plus-maze (EPM) test. The direct binding activity of miRNAs to the 3'-untranslated region (3'-UTR) of the Th gene was measured in HEK-293 cells using a luciferase reporter system. We also examined mRNA and protein expression of TH after intracerebroventricular (ICV) injection of miR-330-5p agomir to SD rats, along with manic-like behaviors. We observed an upregulation in mRNA and protein expression of TH and downregulation in miRNA-325-3p, miR-326-3p, and miR-330-5p expressions in the prefrontal cortex of SD rats, together with increased manic-like behaviors. The luciferase reporter assay showed that miR-330-5p could repress TH expression through direct binding to its target site in the 3'-UTR of Th, whereas miR-326-3p and miR-330-5p could not. In addition, ICV injection of miR-330-5p agomir alleviated the increase in TH expression in the prefrontal cortex of SD rats and manic-like behaviors. TH expression regulation through miR-330-5p may be implicated in the pathophysiology of mania in SD rats.

No NLRP3 Inflammasome Expression in the Ouabain Animal Model of Bipolar Disorder

IntroductionInflammation is believed to play a role in both bipolar illness and unipolar depression. Markers of inflammation are elevated during acute mood episodes. Specifically, gene expressions of the nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3 (NLRP3)-related proteins in peripheral blood have been purported to be upregulated in patients with bipolar disorder. We examined the elaboration of NLRP3 in the ouabain animal model of bipolar disorder. MethodsThe frontal cortex, hippocampus, and basal ganglia tissue from young, male Sprague-Dawley rats who received intracerebroventricular (ICV) ouabain as a model of bipolar disorder or artificial cerebrospinal fluid (aCSF) were examined for NLRP3 utilizing protein immunoblot (Western) analysis. ResultsWe could not demonstrate any NLRP3 in rat brain, but NLRP3 was detected in control from mouse brain and lung.DiscussionThis study demonstrates that the manifestation of manic behavior in rats treated with ICV ouabain is not accompanied by elaboration of NLRP3 inflammasome. This raises the question of the primacy of inflammation in the pathophysiology of mania. If these findings are reproduced in this and other animal models of mania, they would raise important questions about whether inflammation is a primary or secondary phenomenon in the brains of subjects with bipolar disorder.

P2X7 Purinergic Receptor Is Involved in the Pathophysiology of Mania: a Preclinical Study.

The pathophysiology of bipolar disorder remains incompletely elucidated. The purinergic receptor, P2X7 (P2X7R), plays a central role in neuroinflammation, the establishment, and maintenance of microglial activation and neuronal damage/death, all characteristics of bipolar disorder pathology. The present study aims to explore the participation of the P2X7R in a preclinical pharmacological model of mania. We analyzed the modulatory effects of the P2X7R antagonist, brilliant blue, on behavior, monoamines, gene expression, serum purine levels, and cell typing in a pharmacological model of mania induced by D-amphetamine (AMPH) in mice. Our results corroborate an association between the P2X7 receptor and the preclinical animal model of mania, as demonstrated by the decreased responsiveness to AMPH in animals with pharmacologically blocked P2X7R. This study further suggests a possible dopaminergic mechanism for the action of P2X7 receptor antagonism. Additionally, we observed increased peripheral levels of adenosine, a neuroprotective molecule, and increased central expression of Entpd3 and Entpd1 leading to the hydrolysis of ATP, a danger signal, possibly as an attempt to compensate for the damage induced by AMPH. Lastly, P2X7R antagonism in the AMPH model was found to potentially modulate astrogliosis. Our results support the hypothesis that P2X7R plays a vital role in the pathophysiology of mania, possibly by modulating the dopaminergic pathway and astrogliosis, as reflected in the behavioral changes observed. Taken together, this study suggests that a purinergic system imbalance is associated with the AMPH-induced preclinical animal model of mania. P2X7R may represent a promising molecular therapeutic target for bipolar disorder.

Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial.

Immunological abnormalities play a role in the pathophysiology of mania and have been associated with relapse. Probiotic organisms such as Lactobacilli and Bifidobacteria modulate inflammation in humans and animal models. The trial examined whether the administration of probiotic organisms prevents psychiatric rehospitalizations in patients recently discharged following hospitalization for mania. Patients hospitalized for mania (N=66) were randomized after discharge to receive 24weeks of adjunctive probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or adjunctive placebo in a parallel two-group design format. The effect of treatment group on the risk of rehospitalization was calculated using Cox regression models. The modulating effect of systemic inflammation was measured employing an inflammation score based on immunoglobulin levels directed at previously defined antigens. During the 24-week observation period there were a total of 24 rehospitalizations in the 33 individuals who received placebo and eight rehospitalizations in the 33 individuals who received the probiotics (z=2.63, P=.009). Hazard functions indicated that the administration of the probiotics was associated with a significant advantage in time to all psychiatric rehospitalizations (hazard ratio [HR] =0.26, 95% confidence interval [CI] 0.10, .69; P=.007). Probiotic treatment also resulted in fewer days rehospitalized (mean 8.3 vs 2.8days for placebo and probiotic treatment, respectively; χ2 =5.17, P=.017). The effect of the probiotic treatment on the prevention of rehospitalization was increased in individuals with elevated levels of systemic inflammation at baseline. Probiotic supplementation is associated with a lower rate of rehospitalization in patients who have been recently discharged following hospitalization for mania.

Reduction in endogenous cardiac steroids protects the brain from oxidative stress in a mouse model of mania induced by amphetamine

ObjectivesBipolar disorder (BD) is a severe mental illness characterized by episodes of mania and depression. Numerous studies have implicated the involvement of endogenous cardiac steroids (CS), and their receptor, Na+, K+ -ATPase, in BD. The aim of the present study was to examine the role of brain oxidative stress in the CS-induced behavioral effects in mice. MethodsAmphetamine (AMPH)-induced hyperactivity, assessed in the open-field test, served as a model for manic-like behavior in mice. A reduction in brain CS was obtained by specific and sensitive anti-ouabain antibodies. The level of oxidative stress was tested in the hippocampus and frontal cortex by measuring the activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as the levels of antioxidant non-protein thiols (NPSH) and oxidative damage biomarkers thiobarbituric acid reactive substances (TBARS) and protein carbonyl (PC). ResultsAMPH administration resulted in a marked hyperactivity and increased oxidative stress, as manifested by increased SOD activity, decreased activities of CAT and GPx, reduced levels of NPSH and increased levels of TBARS and PC. The administration of anti-ouabain antibodies, which reduced the AMPH-induced hyperactivity, protected against the concomitant oxidative stress in the brain. ConclusionsOur results demonstrate that oxidative stress participates in the effects of endogenous CS on manic-like behavior induced by AMPH. These finding support the notion that CS and oxidative stress may be associated with the pathophysiology of mania and BD.

Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study.

There are no existing longitudinal studies of inflammatory markers and atopic disorders in childhood and risk of hypomanic symptoms in adulthood. This study examined if childhood: (1) serum interleukin-6 (IL-6) and C-reactive protein (CRP); and (2) asthma and/or eczema are associated with features of hypomania in young adulthood. Participants in the Avon Longitudinal Study of Parents and Children, a prospective general population UK birth cohort, had non-fasting blood samples for IL-6 and CRP measurement at the age of 9 years (n = 4645), and parents answered a question about doctor-diagnosed atopic illness before the age of 10 years (n = 7809). These participants completed the Hypomania Checklist at age 22 years (n = 3361). After adjusting for age, sex, ethnicity, socio-economic status, past psychological and behavioural problems, body mass index and maternal postnatal depression, participants in the top third of IL-6 values at 9 years, compared with the bottom third, had an increased risk of hypomanic symptoms by age 22 years [adjusted odds ratio 1.77, 95% confidence interval (CI) 1.10-2.85, p < 0.001]. Higher IL-6 levels in childhood were associated with adult hypomania features in a dose-response fashion. After further adjustment for depression at the age of 18 years this association remained (adjusted odds ratio 1.70, 95% CI 1.03-2.81, p = 0.038). There was no evidence of an association of hypomanic symptoms with CRP levels, asthma or eczema in childhood. Higher levels of systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, suggesting that inflammation may play a role in the pathophysiology of mania. Inflammatory pathways may be suitable targets for the prevention and intervention for bipolar disorder.

Blocking blue light during mania – markedly increased regularity of sleep and rapid improvement of symptoms: a case report

Available pharmacological treatment of mania is insufficient. Virtual darkness therapy (blue light-blocking treatment by means of orange-tinted glasses) is a promising new treatment option for mania. The basis for this might be the recently identified blue light-sensitive retinal photoreceptor, which is solely responsible for light stimulus to the circadian master clock. This is the first case report describing the clinical course of a closely monitored, hospitalized patient in a manic episode first receiving clear-lensed, and then blue light-blocking glasses. A 58-year-old Caucasian man, with bipolar I disorder and three previous manic episodes, was hospitalized during a manic episode. In addition to pharmacological treatment, he was treated with clear-lensed glasses for seven days, then one day without glasses, followed by six days of blue light-blocking glasses. During the entire observational period, he wore an actigraph with internal light sensors. Manic symptoms were unaltered during the first seven days. The transition to the blue-blocking regime was followed by a rapid and sustained decline in manic symptoms accompanied by a reduction in total sleep, a reduction in motor activity during sleep intervals, and markedly increased regularity of sleep intervals. The patient's total length of hospital stay was 20 days shorter than the average time during his previous manic episodes. The unusually rapid decline in symptoms, accompanied by uniform sleep parameter changes toward markedly increased regularity, suggest that blue-blockers might be targeting a central mechanism in the pathophysiology of mania that needs to be explored both in clinical research and in basic science.

In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder

Allopurinol is a drug used primarily to treat hyperuricemia. In patients suffering from acute mania, increased levels of uric acid are observed, and symptom improvements are associated with decreased levels of uric acid. Accordingly, a purinergic dysfunction is plausibly a causative factor in the pathophysiology of mania. The aim of the present study was therefore to investigating whether allopurinol has benefits for patients treated with sodium valproate during acute mania. (Background) A double-blind, placebo-controlled study lasting 4 weeks was performed. The intention-to-treatment population included 57 patients; 50 concluded the study per protocol. Patients suffering from BPD and during acute mania were randomly assigned either to a treatment (sodium valproate 15–20mg/kg+300mg allopurinol twice a day) or to a control condition (sodium valproate 15–20mg/kg+placebo). Experts rated illness severity and illness improvements (Clinical Global impression), and extent of mania via the Young Mania Rating scale. Uric acid levels were assessed at the beginning and end of the study. (Experimental procedures) Compared to the control group, symptoms of mania decreased significantly over time in the treatment group. Uric acid levels declined significantly in the treatment as compared to the control group. Probability of remission after 4 weeks was 23 times higher in the treatment than the control group. Lower uric acid levels after 4 weeks were associated with symptom improvements. (Results) The pattern of results from this double-blind, randomized and placebo-controlled study indicates that adjuvant allopurinol leads to significant improvements in patients suffering from acute mania (Conclusion).

Can Antipsychotic Agents be Considered as Real Antimanic Treatments?

Until now, in various parts of the world, no consensus has been reached with regard to the treatment of acute mania. Controlled clinical trials have at last provided irrefutable evidence for the effectiveness of lithium, which had long been used alone, as well as that of divalproate or its derivatives and, to a lesser extent, carbamazepine (1). In Europe, haloperidol is still the reference compound used in clinical trials while it has never been officially approved in the treatment of mania. In the USA, lithium, divalproate, or second-generation-antipsychotics can be prescribed as first-line treatments. As dopamine was reported to be involved in the pathophysiology of mania in the 1970s and as changes in dopaminergic neurotransmission have consistently been reported in bipolar disorders (BDs), the question of the antimanic properties of antidopaminergic drugs such as antipsychotics is a fair one (2).

In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder

Allopurinol is a drug used primarily to treat hyperuricemia. In patients suffering from acute mania, increased levels of uric acid are observed, and symptom improvements are associated with decreased levels of uric acid. Accordingly, a purinergic dysfunction is plausibly a causative factor in the pathophysiology of mania. The aim of the present study was therefore to investigating whether allopurinol has benefits for patients treated with sodium valproate during acute mania. (Background) A double-blind, placebo-controlled study lasting 4 weeks was performed. The intention-to-treatment population included 57 patients; 50 concluded the study per protocol. Patients suffering from BPD and during acute mania were randomly assigned either to a treatment (sodium valproate 15-20 mg/kg+300 mg allopurinol twice a day) or to a control condition (sodium valproate 15-20 mg/kg+placebo). Experts rated illness severity and illness improvements (Clinical Global impression), and extent of mania via the Young Mania Rating scale. Uric acid levels were assessed at the beginning and end of the study. (Experimental procedures) Compared to the control group, symptoms of mania decreased significantly over time in the treatment group. Uric acid levels declined significantly in the treatment as compared to the control group. Probability of remission after 4 weeks was 23 times higher in the treatment than the control group. Lower uric acid levels after 4 weeks were associated with symptom improvements. (Results) The pattern of results from this double-blind, randomized and placebo-controlled study indicates that adjuvant allopurinol leads to significant improvements in patients suffering from acute mania (Conclusion).

S.04.05 Effect of antidepressant drugs on the heterodimerization of dopamine D2 and somatostatin Sst5 receptors

manic-like behavior. In addition, we evidenced that SD decreased cell proliferation in the dentate gyrus. Interestingly, this effect was acutely rescued by both PKC inhibitors. Taken together, our results support the hypothesis that an overactivation of the PKC signaling system may be crucial for the deficits of neuroplasticity associated with bipolar disorder. Overall, these findings may provide new insights on the pathophysiology of mania and the use of PKC inhibitors as possible novel treatments for mood disorders.

Antibodies to the glutamate receptor in mania

There is evidence that the glutamatergic system is involved in the pathophysiology of mania. Antibodies to the NR2 subunits of the N-methyl-D-aspartate (NMDA) receptor have been shown to adversely affect glutamate functioning. We measured serum antibodies to the NR2 peptide of the NMDA receptor in 60 individuals with different subtypes of mania, including schizoaffective cases, who were assessed at up to three time points. We also measured these antibodies in 295 individuals in other psychiatric groups and in 170 non-psychiatric controls. NR2 antibody levels were compared among groups by multivariate analyses and within the mania group by repeated measures analysis of variance. Individuals with mania had increased levels of antibodies to the NR2 peptide compared to levels in non-psychiatric controls when measured at the time of admission (t = 2.99, p = 0.003) and the time of evaluation (t = 2.57, p = 0.010), but not at follow-up six months later. The levels of antibodies in individuals in other psychiatric groups did not differ significantly from the levels measured in the control population. Within the mania group, there was a significant decrease in antibody levels over the three time points of the study (F = 5.4, df = 2, p = 0.0067). NR2 antibodies are elevated during the acute phase of mania but not at follow-up. Our findings support a role for antibodies to the NMDA receptor in the pathogenesis of acute mania.

O-38 - Downregulation and upregulation of glial connexins may cause synaptic imbalances responsible for the pathophysiology of bipolar disorder

The model of the pathophysiology of bipolar disorder proposed is based on imbalances in tripartite synapses caused by dysregulations of connexin expression in the astrocytic syncytium. If the expression of connexins is downregulated, a compensatory upregulation of astrocytic receptors may occur responsible for the pathophysiology of depression. Conversely, if the expression of connexins is upregulated, the expression of the astrocytic receptors may be downregulated responsible for the pathophysiology of mania. In depression, a relative lack of neurotransmitters exerts a protracted synaptic information processing, whereas in mania a relative increase of neurotransmitters may accelerate synaptic information processing. In addition, the modulatory role of gliotransmitters may be affected in bipolar disorder. Since the dysregulations of connexins impair the astrocytic syncytium, these disorders could be explanatory for cognitive impairment both in depression and in mania. Finally, the testability of this model is discussed.

P.2.e.019 Efficacy of single ketamine infusion in bipolar depression: relationship with serum BDNF

Allopurinol is a drug used primarily to treat hyperuricemia. In patients suffering from acute mania, increased levels of uric acid are observed, and symptom improvements are associated with decreased levels of uric acid. Accordingly, a purinergic dysfunction is plausibly a causative factor in the pathophysiology of mania. The aim of the present study was therefore to investigating whether allopurinol has benefits for patients treated with sodium valproate during acute mania. (Background) A double-blind, placebo-controlled study lasting 4 weeks was performed. The intention-to-treatment population included 57 patients; 50 concluded the study per protocol. Patients suffering from BPD and during acute mania were randomly assigned either to a treatment (sodium valproate 15–20 mg/kg+300 mg allopurinol twice a day) or to a control condition (sodium valproate 15–20 mg/kg+placebo). Experts rated illness severity and illness improvements (Clinical Global impression), and extent of mania via the Young Mania Rating scale. Uric acid levels were assessed at the beginning and end of the study. (Experimental procedures) Compared to the control group, symptoms of mania decreased significantly over time in the treatment group. Uric acid levels declined significantly in the treatment as compared to the control group. Probability of remission after 4 weeks was 23 times higher in the treatment than the control group. Lower uric acid levels after 4 weeks were associated with symptom improvements. (Results) The pattern of results from this double-blind, randomized and placebo-controlled study indicates that adjuvant allopurinol leads to significant improvements in patients suffering from acute mania (Conclusion).

Effect of ouabain on sodium pump alpha-isoform expression in an animal model of mania

While the pathophysiologic mechanisms of bipolar illness are unknown, a dysregulation of electrolytes, particularly intracellular sodium (Na) and calcium (Ca), are thought to contribute to the illness. Ouabain, a potent Na pump inhibitor, administered intracerebroventricularly (ICV), has been used previously to model mania. The current study evaluates the effect of ICV ouabain on Na pump isoform expression in rat brain. Animals received 5 µl ICV of either 10 − 3 M ouabain or artificial cerebrospinal fluid (aCSF). They were then sacrificed 7 days after the ICV injection and specific brain areas were dissected and frozen until the assay (frontal cortex, hippocampus, and basal ganglia). The three isoforms of the alpha subunit of the Na pump that are expressed in the brain were quantified with immunoblot analysis with actin serving as internal control. The behavioral hyperactivity seen in rats receiving ICV ouabain is associated with an increase of expression of the glial-specific alpha2 isoform in the basal ganglia, and the neuron-specific alpha3 isoforms in the frontal cortex. These findings, in association with human post mortem studies finding that alpha2 is underexpressed in the temporal cortex of bipolar subjects, suggest that Na pump isoform expression may be of interest in the pathophysiology of mania.

P.3.c.056 Dose selection of asenapine: application of models based on D2 occupancy to predict efficacy and safety

Allopurinol is a drug used primarily to treat hyperuricemia. In patients suffering from acute mania, increased levels of uric acid are observed, and symptom improvements are associated with decreased levels of uric acid. Accordingly, a purinergic dysfunction is plausibly a causative factor in the pathophysiology of mania. The aim of the present study was therefore to investigating whether allopurinol has benefits for patients treated with sodium valproate during acute mania. (Background) A double-blind, placebo-controlled study lasting 4 weeks was performed. The intention-to-treatment population included 57 patients; 50 concluded the study per protocol. Patients suffering from BPD and during acute mania were randomly assigned either to a treatment (sodium valproate 15–20 mg/kg+300 mg allopurinol twice a day) or to a control condition (sodium valproate 15–20 mg/kg+placebo). Experts rated illness severity and illness improvements (Clinical Global impression), and extent of mania via the Young Mania Rating scale. Uric acid levels were assessed at the beginning and end of the study. (Experimental procedures) Compared to the control group, symptoms of mania decreased significantly over time in the treatment group. Uric acid levels declined significantly in the treatment as compared to the control group. Probability of remission after 4 weeks was 23 times higher in the treatment than the control group. Lower uric acid levels after 4 weeks were associated with symptom improvements. (Results) The pattern of results from this double-blind, randomized and placebo-controlled study indicates that adjuvant allopurinol leads to significant improvements in patients suffering from acute mania (Conclusion).

Late onset bipolar disorder associated with white matter hyperintensities: A pathophysiological hypothesis

Vascular depression is, nowadays, a well-established concept in the literature. However, the possible emergence of late onset bipolar disorder in subjects with no antecedents of mood disorder or after a chronic or recurrent course of unipolar depression constitutes a poorly studied issue, despite its importance in clinical practice. Here, we present the case of a 72-year-old female patient who began to present recurrent major depressive symptoms, resistant to pharmacological treatment, from the age of 58. Three years later, she started to present phases of mania with rapid cycling features. A brain MRI scan showed prominent white matter hyperintensities (WMH). WMH are frequently found in the elderly population, but with greater burden in individuals with hypertension and cerebrovascular disease. WMH impair cortical function and damage the cerebral tissue. WMH have been associated with adult-onset bipolar disorder and late onset depression, and are linked to a worse prognosis of both conditions. The present case report highlights the possibility that vascular-related WMH may provoke late onset bipolar disorder by damaging frontolimbic circuits implicated in the pathophysiology of mania.

Frontal Signal Hyperintensities in Mania in Old Age

Signal hyperintensities (SH) on magnetic resonance (MR) imaging have been associated with increased age and with mood disorders. Frontal and subcortical neuropathology has been implicated in the pathophysiology of mania and bipolar disorders. The authors assessed frontal and subcortical SH in elderly bipolar manic patients and the comparison group, and hypothesized that SH scores would be greater in the patient group. MR imaging was performed in patients aged > or = 60 years with bipolar disorder, mania, and in a same-aged community comparison group. SH were rated blindly using the Boyko system. Frontal deep white matter and basal ganglia SH were assessed in the left and right hemispheres. SH scores were significantly greater in patients (N = 40) than the comparison group (N = 15) in frontal deep white matter (left: p = 0.003; right: p = 0.023) based on Mann-Whitney two-sample exact tests. The SH scores in the subcortical gray regions overlapped in these groups. In patients, higher right frontal SH scores were associated with later age at onset of mania. Frontal deep white matter SH may be increased in elders with bipolar disorder. Further study of the relationship of SH to age at onset in elders is warranted.

P.6.082 An open case study in Italy of oxcarbazepine, an effective mood stabiliser, in patients with drug resistant/intolerant bipolar I disorder

Allopurinol is a drug used primarily to treat hyperuricemia. In patients suffering from acute mania, increased levels of uric acid are observed, and symptom improvements are associated with decreased levels of uric acid. Accordingly, a purinergic dysfunction is plausibly a causative factor in the pathophysiology of mania. The aim of the present study was therefore to investigating whether allopurinol has benefits for patients treated with sodium valproate during acute mania. (Background) A double-blind, placebo-controlled study lasting 4 weeks was performed. The intention-to-treatment population included 57 patients; 50 concluded the study per protocol. Patients suffering from BPD and during acute mania were randomly assigned either to a treatment (sodium valproate 15–20 mg/kg+300 mg allopurinol twice a day) or to a control condition (sodium valproate 15–20 mg/kg+placebo). Experts rated illness severity and illness improvements (Clinical Global impression), and extent of mania via the Young Mania Rating scale. Uric acid levels were assessed at the beginning and end of the study. (Experimental procedures) Compared to the control group, symptoms of mania decreased significantly over time in the treatment group. Uric acid levels declined significantly in the treatment as compared to the control group. Probability of remission after 4 weeks was 23 times higher in the treatment than the control group. Lower uric acid levels after 4 weeks were associated with symptom improvements. (Results) The pattern of results from this double-blind, randomized and placebo-controlled study indicates that adjuvant allopurinol leads to significant improvements in patients suffering from acute mania (Conclusion).

Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex.

The dorsolateral prefrontal cortex (DLPFC) participates in the pathophysiology of mania. In particular, left-sided structural and metabolic abnormalities have been described. Clinical symptoms may be due to hyperactivity of cortical glutamatergic neurons, resulting in increased excitatory neurotransmitter flux and thus enhanced Glx levels. Glutamate/glutamine (Glx) levels were assessed by proton magnetic resonance spectroscopy ((1)H-MRS) in eight acute manic patients compared with age- and gender-matched controls. Manic patients had significantly elevated Glx levels ( t-test; t=-3.1, P=0.008) within the left DLPFC. Our results indicate that the prefrontal cortical glutamatergic system is involved in the pathophysiology of acute mania. This may have implications for the treatment of mania.