Vanessa Cassina Zanatto

Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects.

Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder (BD). This study evaluates plasma levels of the oxidative/energy metabolism markers, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and neuron-specific enolase (NSE) during initial episodes of mania compared to controls in 75 subjects. Two groups of manic subjects (unmedicated n=30, and lithium-treated n=15) were age/gender matched with healthy controls (n=30). TBARS and antioxidant enzymes activity (SOD and CAT) were increased in unmedicated manic patients compared to controls. Conversely, plasma NSE levels were lower during mania than in the controls. In contrast, acute treatment with lithium showed a significant reduction in both SOD/CAT ratio and TBARS levels. These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses, which may be related to dysfunctions on energy metabolism and neuroplasticity pathways. Antioxidant effects using lithium in mania were shown, and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of BD.

Decreased Plasma Brain Derived Neurotrophic Factor Levels in Unmedicated Bipolar Patients During Manic Episode

BACKGROUND Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity and cellular resilience. Brain Derived Neurotrophic Factor (BDNF) gene has been considered an important candidate marker for the development of bipolar disorder and this neurotrophin seems involved in intracellular pathways modulated by mood stabilizers. Also, previous studies demonstrated a role for BDNF in the pathophysiology and clinical presentation of mood disorders. METHODS We investigated whether BDNF levels are altered during mania. Sixty subjects (14 M and 46 F) were selected and included in the study. Thirty patients meeting SCID-I criteria for manic episode were age and gender matched with thirty healthy controls. Young Mania Rating Scale (YMRS) evaluated the severity of manic episode and its possible association with the neurotrophin levels. RESULTS Mean BDNF levels were significantly decreased in drug free/naive (224.8 +/- 76.5 pg/ml) compared to healthy controls (318.5 +/- 114.2), p < .001]. Severity of the manic episode presented a significant negatively correlation to plasma BDNF levels (r= .78; p < .001; Pearson test). CONCLUSIONS Overall, these results suggest that the decreased plasma BDNF levels may be directly associated with the pathophysiology and severity of manic symptoms in BD. Further studies are necessary to clarify the role of BDNF as a putative biological marker in BD.

Increased uric acid levels in drug-naïve subjects with bipolar disorder during a first manic episode

Recent evidence suggests that purinergic system dysfunction may play a role in the pathophysiology and therapeutics of bipolar disorder (BPD). Uric acid is a key nitrogenous end product of purine metabolism. In addition to being a potential marker of treatment response, high levels of uric acid may represent a state marker during mania. In this study, we assessed the presence of purinergic dysfunction in 20 treatment-naïve first episode patients with BPD who were experiencing a manic episode. Patients were matched with 24 healthy controls. We found that acutely manic patients had significantly higher levels of plasma uric acid (4.85+/-1.60 mg/dL) compared to healthy controls (2.96+/-0.63 mg/dL, p<0.001; F=28.1). No association between uric acid levels with severity of manic symptoms was observed. These results support the role of purinergic system dysfunction in BPD early in the course of illness, and suggest that this phenomenon is not the result of chronicity or medication exposure. Overall, our findings suggest a novel mechanism in the pathophysiology of BPD.

Changes in S100B cerebrospinal fluid levels of rats subjected to predator stress

Predator stress is a type of psychogenic stress induced by an innate recognition of threat. S100B, a calcium-binding protein secreted by astrocytes, has been associated with neurotrophic or neurotoxic action in several neuropsychiatric disorders. It has been recently demonstrated that serum S100B levels in rats are increased after stress by immobilization [S. Scaccianoce, P. Del Bianco, G. Pannitteri, F. Passarelli, Relationship between stress and circulating levels of S100B protein, Brain Res. 1004 (2004) 208-11]. This study aimed to measure cerebrospinal fluid (CSF) S100B in rats after an acute stress situation, which is induced by exposure to a predator. S100B was measured in CSF and in hippocampal and cortical slices by ELISA. Forty-three male Wistar rats, aged 70 days, were randomly assigned to handled (control) or stressed groups (exposed to a cat for 5 min). CSF and brain tissue were removed 1 or 24 h after the procedures. Rats exposed to the cat demonstrated a biphasic change in CSF S100B levels. An increase was observed at 1 h after cat exposure, and a decrease was observed 24 h later, although this was not accompanied by changes in S100B content in hippocampus or cerebral cortex. The effectiveness of the stressor used was confirmed by increased freezing response (during cat exposure) and increased anxiety in the plus maze test (1 h after cat exposure). These results indicate that CSF S100B is changed by stress, reinforcing the possibility that this protein is involved in the adaptive response to stress and/or in secondary neuropsychiatric disorders.

Polypharmacy and suicide attempts in bipolar disorder

OBJECTIVE The aim of this study was to assess the association between suicide attempts and the use of multiple drugs in patients with bipolar disorder. METHOD One hundred sixty-nine bipolar disorder outpatients diagnosed using the DSM-IV Structured Clinical Interview were included. Demographic and socioeconomic data, number of medications currently in use, history of suicide attempts, number of years undiagnosed, age of onset and current psychiatric co-morbidities were assessed using a structured questionnaire and DSM-IV criteria. The main outcome measure was the number of psychotropic drugs currently in use. RESULTS Approximately half of all patients (48.5%) presented a history of suicide attempt; 84% were using more than one medication, and 19% were using more than three drugs. The most frequent combinations of drugs used by these patients were: lithium + valproate (17%); lithium + antipsychotics (10%); lithium + valproate + antipsychotics (9%); and antidepressants + any drug (6%). The number of suicide attempts was associated with the use of multiple drugs. CONCLUSIONS Our findings support the notion that the use of combination therapy in bipolar disorder may be related to severity of the BD, such as number of suicide attempts.

Efficacy of milnacipran in treating anxiety symptoms in schizophrenic patients receiving clozapine: a case series study

Sr. Editor, A relação entre morte súbita e esquizofrenia tem recebido crescente atenção. A incidência de morte súbita em pacientes com esquizofrenia é maior do que em indivíduos da população em geral. O fenômeno de morte súbita na esquizofrenia ainda não está totalmente esclarecido; no entanto, uma possível explicação é que este poderia ter causa cardiogênica. A morte súbita cardíaca é definida como morte de causa cardíaca num curto período de tempo (minutos a horas) após o aparecimento dos sintomas iniciais, também podendo ocorrer subitamente sem sintomatologia clínica prévia. Vale notar que muitos indivíduos que morrem subitamente não têm antecedentes de cardiopatia. Dentre os fatores possivelmente relacionados à morte súbita nesses pacientes, podemos destacar: ocorrência de doença cardiovascular, a própria esquizofrenia, o uso de medicamentos antipsicóticos, síndrome metabólica e obesidade, estilo de vida inadequado e tabagismo. Os pacientes com esquizofrenia em tratamento antipsicótico são mais susceptíveis a morrerem subitamente que os pacientes sem tratamento. Várias alterações do ritmo cardíaco têm sido descritas em indivíduos sob tratamento com drogas antipsicóticas, tais como aumento do intervalo QT e baixa variabilidade da freqüência cardíaca. Tal quadro pode ocorrer mesmo com a utilização de doses baixas e em indivíduos que usam tais medicamentos para outros transtornos. Além disso, o risco de morte súbita parece ser maior entre os pacientes que usaram butirofenonas; no entanto, esse risco não difere significativamente dos pacientes que fazem uso de outros medicamentos antipsicóticos. Embora a morte súbita possa decorrer do aumento de peso associado ao uso de medicações e anormalidades metabólicas associadas, que incluem hiperglicemia, diabetes mellitus e dislipidemia, vale ressaltar que nem todos os medicamentos antipsicóticos de 2a geração apresentam a mesma probabilidade de desencadear esse efeito adverso, uma vez que a ziprasidona, o aripripazol e a risperidona estão associados com menor ganho de peso quando comparados com a quetiapina, olanzapina e clozapina. Em conclusão geral, a esquizofrenia é uma doença crônica que está associada com um amento da mortalidade. Apesar da morte súbita não ser considerada uma das principais causas de morte em pacientes com esquizofrenia, as alterações autonômicas e suas interações com drogas antipsicóticas devem ser avaliadas com mais atenção pelos clínicos. Como os medicamentos antipsicóticos de 1 e 2 geração podem alterar o ritmo cardíaco e o eletrocardiograma (QT longo e baixa variabilidade da freqüência cardíaca), o médico deve estar atento aos efeitos colaterais desses fármacos, não somente pelo risco de morte súbita, mas pela piora da qualidade de vida que eles acarretam aos pacientes. Carta aos editores