Effect of Initial Ziprasidone Dose on Treatment Outcome of Korean Patients with Acute Manic or Mixed Episodes

OBJECTIVE: We investigated the efficacy and tolerability of ziprasidone combined with divalproex to determine the relationship between the initial dose of ziprasidone and the treatment effect among Korean patients with acute bipolar manic or mixed disorders. METHODS: This study was a 6-week, open-label, prospective investigation of Korean patients with an acute manic or mixed episode of bipolar disorder. Sixty-five patients were recruited. The patients were categorized based on the initial dose of ziprasidone as follows: low (20-79 mg/day) and standard (80 mg/day). Ziprasidone was given in combination with divalproex in flexible doses, according to the clinical response and tolerability. RESULTS: The response and remission rates were significantly higher in the standard-dose group than the low-dose group. The combination of ziprasidone and divalproex was well-tolerated and adverse events were mostly mild with no statistically significant increase in body weight. CONCLUSION: The results of this study showed that a standard starting dose of ziprasidone in combination with divalproex for bipolar disorder is more effective than a low starting dose.

Influence of NMDA and non-NMDA antagonists on acute and inflammatory pain in the trigeminal territory: a placebo control study / Influência dos antagonistas dos receptores NMDA e não-NMDA sobre a dor aguda e inflamatória ao nível do território do trigêmeo: um estudo placebo controlado

NMDA and non-NMDA receptors are involved in spinal transmission of nociceptive information in physiological and pathological conditions. Our objective was to study the influence of NMDA and non-NMDA receptor antagonists on pain control in the trigeminal system using a formalin-induced orofacial pain model. Motor performance was also evaluated. Male Rattus norvegicus were pre-treated with topiramate (T) (n=8), memantine (M) (n=8), divalproex (D) (n=8) or isotonic saline solution (ISS) (n=10) intraperitoneally 30 minutes before the formalin test. Formalin 2.5 percent was injected into the right upper lip (V2 branch) and induced two phases: phase I (early or neurogenic) (0-3 min) and phase II (late or inflammatory) (12-30 min). For motor behavior performance we used the open-field test and measured latency to movement onset, locomotion and rearing frequencies, and immobility time. Pre-treatment of animals with M and D only attenuated nociceptive formalin behavior for phase II. T increased locomotion and rearing frequencies and reduced immobility time. Treatment with M increased immobility time and with D reduced locomotion frequency. Our results showed that the NMDA antagonist (M) is more potent than the non-NMDA antagonists (D and T) in the control of pain in the inflammatory phase. The non-NMDA topiramate improved motor performance more than did D and M, probably because T has more anxiolytic properties.

Receptores NMDA e não-NMDA estão envolvidos na transmissão das informações nociceptivas em condições fisiológicas e patológicas. Com o objetivo de estudar a influência dos antagonistas dos receptores NMDA e não-NMDA sobre o controle de dor no sistema trigeminal utilizamos modelo de dor orofacial induzida pela formalina. Testes de desempenho motor foram também avaliados. Ratos machos da espécie Rattus norvegicus foram tratados com topiramato (T) (n=8), memantina (M) (n=8), divalproato de sódio (D) (n=8) ou solução salina isotônica (SSI) (n=10), por via intraperitoneal, 30 minutos antes dos testes com a formalina. Formalina 2.5 por cento foram injetadas na região do lábio superior dos animais (segundo ramo do trigêmeo) induzindo comportamento em duas fases distintas: fase I (precoce ou neurogênica) (0-3 min ) e fase II (tardia ou inflamatória) (12-30 min). Para avaliação da atividade motora utilizou-se o teste do campo aberto mensurando-se a latência para o início dos movimentos, número de casas andadas, freqüência de levantamentos e tempo de imobilidade. Animais pré-tratados com M e D atenuaram a fase inflamatória do teste da formalina. O T aumenta o número de casas andadas, freqüência de levantamentos e reduz o tempo de imobilidade. Nossos resultados mostram que o antagonista NMDA é mais potente do que os antagonistas não-NMDA para o controle da fase inflamatória da dor. O topiramato entretanto aumenta a atividade motora provavelmente porque apresente propriedades ansiolíticas.

Actual bioavailability of divalproex sodium extended-release tablets and its clinical implications

Divalproex sodium extended-release dosage form (divalproex-ER) has been promoted as innovative formulation for the treatment of epilepsy and manic disorders, and for migraine headache prevention, with the advantage of being dosing once a day. Due to a significant decreasing in the peak-trough fluctuation of plasma valproic acid levels, in comparison with the twice-daily dosing of conventional delayed-release formulations (divalproex-DR), concentration-dependent side effects would be prevented. However the main constraint for divalproex-ER usage is the need to be administered in a higher daily dose, because of its lower bioavailability, in order to prevent eventual breakthrough seizures when patients are switched from the twice-daily divalproex DR regimen. Taking into account free plasma drug levels, divalproex ER/DR relative bioavailability could be assessed as low as 75 percent in fasting condition. In order to overcome the need of increase divalproex-ER daily dose, maintenance of the twice-daily regimen is suggested. Divalproex-ER administered every 12 hours not only increases steady state trough concentration to a higher value in comparison with divalproex-DR, avoiding inefficacy of the treatment, but also achieves the safest manner to treat patients with valproic acid because of reaching practically a plateau profile of drug levels.

Divalproato de sodio de liberación prolongada (divalproex-ER) es un producto innovador que ha sido promovido tanto para el tratamiento de la epilepsia y de los desórdenes maníacos como también para la prevención de la migraña, con la ventaja de poder administrarse una sola vez al día. Dado que la fluctuación de niveles plasmáticos de ácido valproico resulta menor que la originada por la administración dos veces al día del producto convencional de liberación retardada (divalproex-DR), se estarían previniendo los efectos secundarios dependientes de la concentración del fármaco. Sin embargo, y considerando la menor biodisponibilidad del producto, el uso de divalproex-ER tiene el principal inconveniente de necesitar una mayor dosis diaria a los efectos de evitar una eventual reaparición de crisis cuando los pacientes cambian de tratamiento desde divalproex-DR. Teniendo en cuenta los niveles plasmáticos libres del fármaco, la biodisponibilidad relativa divalproex ER/DR podría afirmarse que sea aún más baja, tanto como 75 por ciento cuando los estudios son realizados en ayunas. A los efectos de no incrementar la dosis diaria de divalproex-ER se sugiere mantener un régimen de administración cada 12 horas. La administración de divalproex-ER dos veces al día no sólo incrementa las concentraciones de valle, respecto a divalproex-DR, sino que logra un perfil de niveles de ácido valproico prácticamente de meseta, lográndose así un tratamiento eficaz y con la mayor seguridad para los pacientes.

Body Mass Index(BMI) Changes during Combination Therapy with Mood Stabilizers and Antipsychotics in Acute Mania / 대한정신약물학회지

OBJECTIVE: To estimate changes in body mass index (BMI) during the treatment of acute manic patients, we retrospectively analyzed the medical records of patients admitted to Inha University Medical Center between January 1997 and December 2005. METHODS: Ninety-nine patients were divided into six groups according to their treatment regimens: monotherapy with lithium or divalproex and combination therapy with lithium and haloperidol, lithium and olanzapine, divalproex and haloperidol, or divalproex and olanzapine. Their demographic and clinical characteristics were assessed on admission, and the BMI was measured on admission and every week for 4 weeks after treatment. RESULTS: The combination therapy groups of lithium and olanzapine and divalproex and olanzapine had significant increases in BMI in proportion to the exposure time to medication (p=0.000), and there was no significant difference in the increase in BMI between these two groups. The normal weight group tended to have a greater increase in BMI than the overweight and obesity groups (p=0.078). CONCLUSION: The combination of a mood stabilizer (lithium or divalproex) with olanzapine is associated with a greater increase in BMI than are other treatment regimens in the acute manic phase of bipolar I disorder. More attention to weight gain is needed in the prescription of medications in acute manic patients and further studies are needed.

Effects of Divalproex sodium for Visual Cortex Excitability in Migraine: A Study Using Transcranial Magnetic Stimulation

BACKGROUND: The pathophysiology of migraine has not been fully understood. One of the hypotheses is cortical hyperexcitability. Transcranial magnetic stimulation (TMS) is a noninvasive electrophysiologic tool for the investigation of cortical excitability. Divalproex sodium may prevent migraine attacks by increasing the GABA-ergic tone. We examined the phosphene generation using TMS in migraine patients in order to investigate the cortical excitability and its response by valproate prophylaxis. METHODS: We applied TMS to 27 migraineurs and 27 control subjects. TMS was performed by a Magstim Rapid Stimulator connected to a 70 mm figure-of-eight coil to examine the phosphene threshold between migraineurs and controls on primary (V1) and bilateral secondary (V5) visual cortices. Twelve migraine patients completed a one month administration of divalproex sodium 500 mg/day. We compared the phosphene threshold between pre- and post-treatment with devalproex sodium in these patients. RESULTS: The prevalence of the phosphene generation was significantly higher in migraineurs compared with controls in V1 and V5. The phosphene average thresholds were significantly lower in migraineurs compared with controls in V1 and V5. The phosphene average thresholds in the same areas were significantly higher in post-treatment compared with pre-treatment in migraineurs. CONCLUSIONS: The differences of the phosphene threshold in the visual cortex between migraineurs and controls comply with the theory of cortical hyperexcitability for the pathophysiology of migraine. Valproate might play a significant role in the prophylaxis of migraine by decreasing cortical hyperexcitability.

Effectiveness and Tolerability of Topiramate Versus Divalproex in Bipolar Mania / 대한정신약물학회지

Mood stabilizers and atypical antipsychotics are commonly combined for the treatment of bipolar mania. The aim of this study was to compare the effectiveness and tolerability of topiramate and divalproex in combination with risperidone for treating acute mania patients in a naturalistic treatment setting. Seventy-four patients who met the DSM-IV criteria for bipolar mania were enrolled in this study. In order to assess the efficacy and the extrapyramidal symptoms, the Young Mania Rating Scale (YMRS), Clinical Global Impression (CGI) and Simpson-Angus Rating Scale were measured at the baseline and at weeks 1, 3 and 6. From the baseline to the endpoint, the YMRS and CGI scores were reduced by 67.9% and 56.6% in the topiramate group. The YMRS and CGI scores were also reduced by 63.7% and 58.2% in the divalproex group. The weight and BMI increased significantly by 3.6% and 3.3% from the baseline to the endpoint in the divalproex group, while they decreased by 0.4% and 0.5%, respectively, with no significant difference in the topiramate group. There were no serious adverse events in either group. Topiramate is effective and tolerable for treating acute mania, and may also be a promising alternative to a weightgain liable mood stabilizer such as divalproex.

Effects of the Divalproex Sodium on Cortical Hyperexcitability in Migraine Patients Chung-Ang University,Pildong Hospital

BACKGROUND: Cortical hyperexcitability is proposed to be the putative basis for the physiological disturbances in migraine. Recent studies have demonstrated that divalproex sodium effectively prevents migraine. The cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) reflects the cortical inhibition of the central motor pathway. METHODS: We studied the CSP of both first dorsal interossei muscles evoked by TMS in 15 migraine patients and 15 normal subjects. As a prophylactic therapy, 15 migraine patients were treated with divalproex sodium 500~750 mg/day. After 3 months, we studied the CSP in migraine patients for the purpose of comparing with results before medication. RESULTS: The CSP was shorter in migraine patients than in controls (135.8+/-27.8 msec vs 203.7+/-32.2 msec, p<0.001). After treatment with divalproex sodium, the CSP was significantly prolonged in migraine patients (196.9+/-31.0msec, p=0.001). CONCLUSIONS: The shortened CSP in migraine patients suggests increased excitability of the cortical neuron in migraine. The prolonged CSP after medication in migraine patients suggests that the divalproex sodium may play a role in the prophylaxis of migraine by decreasing cortical neuronal hyperexcitability. (J Korean Neurol Assoc 19(5):489~493, 2001)