[Kynurenine pathway in bipolar disorder].

Bipolar disorder (BD) is a chronic psychiatric illness which, among other things, is characterized by cerebral dysfunctions, cognitive disorders and sleep disturbances. The neurobiological basis of these processes remains unclear. In recent years, studies have focused on the role of immune-inflammatory mechanisms induced by the tryptophan metabolism pathway (TRP) and the kynurenine pathway (KYN). Emerging data correlates TRP and KYN metabolites with BD's pathophysiology and course. The purpose of this review is to search the available data on the involvement of KYN's pathway in the pathophysiology, the clinical presentation and the course of BD. A systematic literature review was conducted using web-based search engines provided by PubMed (for Medline database) and Google Scholar. The search languages were English and Greek and the entries Key phrases used for the research were: bipolar disorder, depression, mania, tryptophan, kynurenine pathway, cognitive dysfunction, sleep disorder, neuroimmunology, neuroinflammation manuscripts written or published in English and Greek language. The KYN pathway is actively involved in the pathophysiology of BD. The increase in neurotoxic weight of the neuroprotective derivatives of the pathway is associated with cognitive impairment that accompany the clinical presentation of the disease. In addition, some of these metabolites are also suspected of sleep disorders in BD. Further studies are needed to investigate the mechanisms involved. The KYN pathway is a highly interesting field of encounter and interaction of the immune inflammatory system with the CNS, both involved in the pathophysiology of BD in a variety of ways. Future research can focus on clarifying the role of the metabolites of this pathway, potentially highlighting new therapeutic goals. Additionally, consideration could be given to approaching the metabolites of the KYN pathway as biomarkers for early detection, staging and monitoring of BD patients.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Major depression amid financial crisis in Greece: Will unemployment narrow existing gender differences in the prevalence of the disorder in Greece?

Rises in unemployment as a corollary to the global economic crisis may impinge on the prevalence of depression disproportionally for the two genders. Therefore, differences in the prevalence of the disorder as a function of gender and age were explored in four nationwide surveys in Greece in 2008, 2009, 2011 and 2013. Results indicate that in 2013, men of productive age had a higher prevalence of major depression than women, in contrast to the epidemiology of the disorder. The psychiatry community should be in tune to future changes in the mental health landscape elicited by the social fermentation processes of the global recession.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Brain functional connectivity and the pathophysiology of schizophrenia.

In the last decade there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neuronal responses are associated with synchronized oscillatory activity in various frequency ranges suggesting a functional mechanism of neural oscillations in cortical networks. In addition to their role in normal brain functioning, there is increasing evidence that altered oscillatory activity may be associated with certain neuropsychiatric disorders, such as schizophrenia. Consequently, disturbances in neural synchronization may represent the functional relationship of disordered connectivity of cortical networks underlying the characteristic fragmentation of mind and behavior in schizophrenia. In recent studies the synchronization of oscillatory activity in the experience of characteristic symptoms such as auditory verbal hallucinations and thought blocks have been studied in patients with schizophrenia. Studies involving analysis of EEG activity obtained from individuals in resting state (in cage Faraday, isolated from external influences and with eyes closed). In patients with schizophrenia and persistent auditory verbal hallucinations (AVHs) observed a temporary increase in the synchronization phase of α and high θ oscillations of the electroencephalogram (EEG) compared with those of healthy controls and patients without AVHs . This functional hyper-connection manifested in time windows corresponding to experience AVHs, as noted by the patients during the recording of EEG and observed in speech related cortical areas. In another study an interaction of theta and gamma oscillations engages in the production and experience of AVHs. The results showed increased phase coupling between theta and gamma EEG rhythms in the left temporal cortex during AVHs experiences. A more recent study, approaches the thought blocking experience in terms of functional brain connectivity. Thought blocks (TBs) are characterized by regular interruptions of the flow of thought. Outward signs are abrupt and repeated interruptions in the flow of conversation or actions while subjective experience is that of a total and uncontrollable emptying of the mind. In the very limited bibliography regarding TB, the phenomenon is thought to be conceptualized as a disturbance of consciousness that can be attributed to stoppages of continuous information processing due to an increase in the volume of information to be processed. In an attempt to investigate potential expression of the phenomenon on the functional properties of electroencephalographic (EEG) activity, an EEG study was contacted in schizophrenic patients with persisting auditory verbal hallucinations (AVHs) who additionally exhibited TBs. Phase synchronization analyses performed on EEG segments during the experience of TBs showed that synchrony values exhibited a long-range common mode of coupling (grouped behavior) among the left temporal area and the remaining central and frontal brain areas. These common synchrony-fluctuation schemes were observed for 0.5 to 2 s and were detected in a 4-s window following the estimated initiation of the phenomenon. The observation was frequency specific and detected in the broad alpha band region (6-12 Hz). The introduction of synchrony entropy (SE) analysis applied on the cumulative synchrony distribution showed that TB states were characterized by an explicit preference of the system to be functioned at low values of synchrony, while the synchrony values are broadly distributed during the recovery state. The results indicate that during TB states, the phase locking of several brain areas were converged uniformly in a narrow band of low synchrony values and in a distinct time window, impeding thus the ability of the system to recruit and to process information during this time window. The results of this study seem to have greater importance on neuronal correlation of consciousness. The brain is a highly distributed system in which numerous operations are executed in parallel and that lacks a single coordinating center. This raises the question of how the computations occurring simultaneously in spatially segregated processing areas are coordinated and bound together to give rise to coherent percepts and actions. One of the coordinating mechanisms appears to be the synchronization of neuronal activity by phase locking of self-generated network oscillations. This led to the hypothesis that the cerebral cortex might exploit the option to synchronize the discharges of neurons with millisecond ` theoretical formulations of the binding-by-synchrony hypothesis were proposed earlier by Milner (1974), but the Singer lab in the 1990s was the first to obtain experimental evidence supporting the potential role of synchrony as a relational code. The results concerning the functional connectivity of the brain during TBs further support the hypothesis of phase synchronization as a key mechanism for neuronal assemblies underlying mental representations in the human brain.

The effect of aliskiren versus ramipril-based treatment on the Ambulatory Arterial Stiffness Index in hypertensive patients.

AIM: Aim of the present study was to compare the effectiveness of two renin-angiotensin-aldosterone system inhibitors in arterial stiffness reduction in previously untreated hypertensive patients. METHODS: In this open label study, 154 naïve, or not treated in the last six months hypertensive patients were randomly assigned to receive aliskiren 300 mg or ramipril 5 mg daily. Six weeks after the initiation of treatment, patients were evaluated for blood pressure (BP) control. Patients with SBP ≥140 and/or DBP ≥90 mmHg were assigned to an adjunct of 25 mg hydrochlorothiazide as combination treatment. A re-evaluation of BP control was done after another 6 weeks. Individuals with BP ≥140/90 mmHg were further administered amlodipine 5 mg. The final evaluation was performed six months after the start of the study. Twenty four-hour ambulatory blood pressure monitoring was carried out and the ambulatory arterial stiffness index (AASI) was calculated at baseline and after 6 months of treatment. RESULTS: Aliskiren-based therapy, as compared with ramipril-based therapy reduced BP to a similar degree: 13±11 vs. 12±11 mmHg reduction in systolic (P=0.34) and 8±7 vs. 7±7 mmHg reduction in diastolic BP (P=0.44). AASI was reduced by 0.04±0.1 in the aliskiren group and by 0.02±0.2 in the ramipril group. AASI reduction did not differ significantly in the two groups (P=0.13). CONCLUSION: In hypertensive patients, aliskiren-based treatment as well as ramipril-based treatment appears to have a beneficial effect on arterial stiffness. As arterial stiffness is an important modifiable risk factor, our findings highlight the value of aliskiren beyond BP lowering properties.

Changes in thenar muscle tissue oxygen saturation assessed by near-infrared spectroscopy during weaning from mechanical ventilation.

BACKGROUND: Tissue oxygen saturation (StO2) measured by near-infrared spectroscopy (NIRS) has been used to provide information on local tissue oxygenation in different clinical settings. This study aims to determine the effect of weaning from mechanical ventilation on thenar muscle StO2. METHODS: In consecutive critically ill mechanically ventilated patients, StO2 at the thenar eminence, along with a vascular occlusion test (VOT), were measured by NIRS, on mechanical ventilation and during a 2-hour T-piece spontaneous breathing trial (SBT). Hemodynamic, gas exchange and respiratory variables were recorded. RESULTS: Forty-four patients were included in this study, 25 tolerated the SBT and 19 failed. On mechanical ventilation, no differences in any measured variable were observed between patients who succeeded or failed. Two minutes after SBT start, StO2 was decreased in patients who failed whereas it did not change in patients who succeeded (P<0.001). For all data, 2 minutes after the start of SBT, StO2 significantly correlated with SaO2 (r=0.32, P=0.037) and with the respiratory frequency/tidal volume (f/VT) index (r=-0.34, P=0.023). VOT-derived StO2 downslope and StO2 upslope did not change significantly along the SBT test. The maximum StO2 value, its ratio to minimum StO2, and the post-VOT StO2 value decreased significantly in patients who failed whereas no change was found in those who succeeded the SBT (P=0.003, P=0.025 and P<0.001 respectively). StO2 and f/VT at the second minute of SBT yielded a receiver operator characteristics curve area value of 0.77 and 0.80, P=0.002, respectively, in detecting the SBT outcome. CONCLUSION: SBT failure was associated with a significant impairment of thenar muscle StO2. A decrease of StO2 at 2 minutes after disconnection from the ventilator was associated with SBT failure. Further validation is warranted.

Non-invasive assessment of the microcirculation in critically ill patients.

Sepsis is associated with abnormalities of muscle tissue oxygenation and of microvascular function. We investigated whether the technique of near-infrared spectroscopy can evaluate such abnormalities in critically ill patients and compared near-infrared spectroscopy-derived indices of critically ill patients with those of healthy volunteers. We studied 41 patients (mean age 58 +/- 22 years) and 15 healthy volunteers (mean age 49 +/- 13 years). Patients were classified into one of three groups: systemic inflammatory response syndrome (SIRS) (n = 21), severe sepsis (n = 8) and septic shock (n = 12). Near-infrared spectroscopy was used to continuously measure thenar muscle oxygen saturation before, during and after a three-minute occlusion of the brachial artery via pneumatic cuff. Oxygen saturation was significantly lower in patients with SIRS, severe sepsis or septic shock than in healthy volunteers. Oxygen consumption rate during stagnant ischaemia was significantly lower in patients with SIRS (23.9 +/- 7.7%/minute, P < 0.001), severe sepsis (16.9 +/- 3.4%/minute, P < 0.001) or septic shock (14.8 +/- 6%/minute, P < 0.001) than in healthy volunteers (35.5 +/- 10.6%/minute). Furthermore, oxygen consumption rate was significantly lower in patients with septic shock than patients with SIRS. Reperfusion rate was significantly lower in patients with SIRS (336 +/- 141%/minute, P < 0.001), severe sepsis (257 +/- 150%/minute, P < 0.001) or septic shock (146 +/- 101%/minute, P < 0.001) than in healthy volunteers (713 +/- 223%/minute) and significantly lower in the septic shock than in the SIRS group. Near-infrared spectroscopy can detect tissue oxygenation deficits and impaired microvascular reactivity in critically ill patients, as well as discriminate among groups with different disease severity.

Predisposing factors for critical illness polyneuromyopathy in a multidisciplinary intensive care unit.

OBJECTIVE: To investigate risk factors of critical illness polyneuromyopathy (CIPM) in a general multidisciplinary intensive care unit (ICU). PATIENTS AND METHODS: Prospective observational study in a 28-bed university multidisciplinary ICU. Four hundred and seventy-four (323 M/151 F, age 55 +/- 19) consecutive patients were prospectively evaluated. All patients were assigned admission Acute Physiology and Chronic Health Evaluation (APACHE II; 15 +/- 7) and Sequential Organ Failure Assessment (SOFA; 6 +/- 3) scores and were subsequently evaluated for newly developed neuromuscular weakness. Other potential causes of new-onset weakness after ICU admission were excluded before CIPM was diagnosed. RESULTS: Forty-four (23.8%) of 185 patients developed generalized weakness that met the criteria for CIPM. Patients with CIPM had higher APACHE II (18.9 +/- 6.6 vs 15.6 +/- 6.4, P = 0.004) and SOFA scores (8.4 +/- 2.9 vs 7.1 +/- 2.9, P = 0.013). According to multivariate logistic regression analysis, the following risk factors were independently associated with the development of CIPM: severity of illness at the time of ICU admission, administration of aminoglycoside antibiotics and high blood glucose levels. Analysis according to severity of illness stratification revealed the emergence of Gram (-) bacteremia as the most important independent predisposing factor for CIPM development in less severely ill patients. CONCLUSIONS: CIPM has a high incidence in the ICU setting. Our study revealed the association of aminoglycosides, hyperglycemia and illness severity with CIPM development, as well as the association between Gram (-) bacteremia and development of CIPM in less severely ill patient population.

Propofol-induced hyperamylasaemia in a general intensive care unit.

This study examined the incidence of hyperamylasaemia, in the absence of other plausible causes of pancreatic dysfunction, in intensive care unit (ICU) patients who received propofol. One-hundred-and-seventy-two consecutive patients of a general ICU who stayed for more than 24 hours were studied. Patients with a diagnosis consistent with elevated serum amylase levels at admission were excluded from the study, as were patients who had received medications known to raise serum amylase levels. Forty-four patients 53 +/- 20 years of age and median duration of ICU stay of five days (range two to 55) were eligible. Thirty of those, aged 54 +/- 21 years and median duration of ICU stay of five days (range two to 27) received continuous infusion of propofol for sedation (maximum dose 45 microg/kg/min). Of the 30 patients who received propofol, 16 (53%) developed hyperamylasaemia (125 to 466 IU/l) after two to nine days of continuous infusion. Liver and kidney function remained normal throughout the observation period. Of the 14 patients who did not receive propofol (aged 51 +/- 18 years), only two (14%) developed hyperamylasaemia, a significantly lower incidence (P = 0.021). Propofol infusion is associated with biochemical evidence of pancreatic injury. Amylase levels monitoring of propofol-sedated patients is warranted.

The influence of levodopa and the COMT inhibitor on serum vitamin B12 and folate levels in Parkinson's disease patients.

Serum folate and vitamin B12 levels were measured in 67 consecutive Parkinson's disease patients treated either with levodopa + dopa decarboxylase inhibitor (DDC-i) plus catechol-O-methyltransferase inhibitors (COMT-i) or only with levodopa + DDC-i. The data were compared to 67 age-matched controls. Our findings show that levodopa-treated Parkinson's disease patients have low folate (p < 0.0007) and vitamin B12 levels (p < 0.0003). They also demonstrate that the addition of a COMT-i to levodopa + DDC-i treatment causes lower serum vitamin B12 (p < 0.03) and folate levels (p < 0.005) than levodopa + DDC-i treatment alone. We suggest supplementary treatment with vitamin B12 and folic acid in these situations.

Acute psychosis due to treatment with phenytoin in a nonepileptic patient.

The development of psychosis related to antiepileptic drug treatment is usually attributed to the interaction between the epileptic brain substratum and the antiepileptic drugs. The case of a nonepileptic patient who developed psychosis following phenytoin treatment for trigeminal neuralgia is described. This case suggests that the psychotic symptoms that occur following phenytoin treatment in some epileptic patients may be the direct result of medication, unrelated to seizures.

Manic symptoms induced by olanzapine.

We present the case of a never medicated patient with a diagnosis of DSM-IV paranoid schizophrenia in which olanzapine therapy induced manic symptoms. The latter remitted after drug discontinuation.

The Greek version of the calgary depression scale for schizophrenia.

The aim of this study was to evaluate the reliability and validity, as well as the specificity, of the Greek version of the Calgary Depression Scale for Schizophrenia (CDSS). Schizophrenic inpatients consecutively admitted at the Eginition Hospital, University of Athens, were included in the study. Patients were assessed on admission using the CDSS, the Hamilton Depression Rating Scale (HDRS), the Positive and Negative Syndrome Scale (PANSS), the Rating Scale for Extrapyramidal Side Effects (RSESE), the Rating Scale for Drug-Induced Akathisia (RSDIA) and the Abnormal Involuntary Movement Scale (AIMS). The CDSS was found to have a high inter-rater reliability, as well as test-retest reliability or split-half reliability. The internal consistency of the CDSS was good (a=0.87). There were positive correlations between the CDSS and the HDRS, or the depression cluster of the PANSS. The mean score on the CDSS showed no significant correlations with that of the PANSS negative subscale (r=0.123); a negative but not significant correlation with that of the PANSS positive subscale (r=-0.036); a weak correlation with that of the PANSS general psychopathology subscale (r=0.218); and no significant correlations with that of the RSESE (r=0.197), the RSDIA (r=0.160) or the AIMS (r=0.031). Our results give further support to the reliability, the validity, and the specificity of the CDSS.

Convulsive status epilepticus following abrupt high-dose benzodiazepine discontinuation.

The misuse of benzodiazepines (BNZ)s may result in serious side effects. Three cases of convulsive status epilepticus (CSE) following abrupt discontinuation of long-term use of 25 mg of lorazepam in one patient and more than 20 mg of flunitrazepam in two patients are presented; they were non-epileptics and free of other high-risk factors for seizures. A favorable outcome for all three cases was noted. They remain free of seizures without antiepileptic treatment. Nevertheless, because of the extensive use of benzodiazepines, such rare high-risk side effects must be emphasized.

Neuroendocrine responsivity to clomipramine challenge test in neuroleptic naive psychotic patients before and after treatment with haloperidol.

The prolactin, cortisol and growth hormone (GH) responses to intravenous administration of 25 mg clomipramine (CMI) were studied in young male psychotic patients who had never received neuroleptics and suffered from schizophrenia (13 patients), delusional disorder (three patients) or schizoaffective disorder (one patient). The test was repeated after 1 month in 16 patients who were hospitalized and treated with haloperidol in doses appropriate for best clinical response (range: 7.5-40 mg daily). Symptomatology was assessed by the Brief Psychiatric Rating Scale (BPRS). There was no association of the side effects caused by the administration of CMI (nausea and emesis) to the GH responses. The side effects appeared significantly less in the after treatment trials. Treatment with haloperidol did not influence the response patterns of the three hormones. An indication that high haloperidol doses may inhibit the prolactin response to CMI was obtained when the data were compared between low (7.5-10 mg/day, mean 9.7) and high (15-40 mg/day, mean 22.0) dose subgroups. Significant positive correlations were found between the prolactin and cortisol responses to CMI in the drug-free state, and the scores in the positive symptoms subscale of the BPRS. The degree of improvement did not correlate to any of the hormonal data.

Acute tolerance to the excitatory effects of opioids in the rat hippocampus.

Prolonged iontophoretic administrations of delta- and mu-selective opioid receptor agonists were conducted in the hippocampus of rats, in order to study the possible development of acute tolerance to the excitatory effects of the opioids. Acute tolerance (AT) to the excitatory effects of the delta-selective opioid receptor agonist Tyr-D-Ser-Gly-Phe-Leu-Thr (DSLET) was observed when the drug was applied locally for 3-5 min in the CA1 hippocampal pyramidal neurons. The acute tolerance was expressed as a decrease in the commissurally evoked spike responsiveness during peptide's administration and led to a long-lasting potentiation of the population spike (PS) upon its withdrawal. In all cases, where AT and spike potentiation were evident, the population excitatory postsynaptic potential (pEPSP) remained unaltered. Pharmacological studies of AT and long-lasting spike potentiation showed the following: (1) the nonselective opioid receptor antagonist, naloxone, while effective in blocking the excitatory effects of DSLET when applied prior and during the application of the latter, failed to exhibit any effect on the long-lasting potentiating effect of the opioid; and (2) during the spike potentiation phase, administration of DSLET exhibited a depressant effect towards baseline values. This depressant effect of the opioid was evident 2-3 min from the beginning of the application and was completely antagonized by naloxone. The above results show that the development of acute tolerance to the excitatory effects of the DSLET led to long-lasting spike potentiation, which manifests a withdrawal phenomenon.

Dimensionality alterations of the hippocampal electroencephalographic activity following the induction of long-term potentiation in rats.

In the present in vivo experimental study the complexity alterations of the hippocampal electroencephalographic (EEG) activity were investigated prior and during the maintenance phase of long-term potentiation (LTP), using analytical methods based on the recent concepts of deterministic chaos. LTP was induced in the hippocampal dentate hilus after stimulation of the medial perforant path of the rat's brain. During the experimental procedure hippocampal EEG epochs were recorded prior and after the induction of LTP. Dimensionality computations performed on these epochs showed a maintained relative reduction in the correlation dimension during the maintenance phase of LTP. This result might suggest that different functional states of the brain are governed by different degrees of complexity and that the altered efficacy in the information process, as it is achieved by the induction of LTP, modifies the spontaneous EEG activity of the potentiated hippocampal area in a plastic manner.