Antimanic efficacy of topiramate in 11 patients in an open trial with an on-off-on design.

BACKGROUND: A series of open studies suggests that topiramate has efficacy in bipolar disorder. To further investigate the potential value of topiramate as an antimanic agent, we conducted an open trial in 11 manic patients. METHOD: Eleven patients with bipolar I disorder with an acute manic episode (DSM-IV) were treated with a mood stabilizer and/or antipsychotics in sufficient and fixed doses. All had a Young Mania Rating Scale (YMRS) score of at least 24 (mean +/- SD = 33.5+/-8.1). Topiramate was added after stable plasma levels of concomitant mood stabilizers had been reached and was titrated within 1 week to a final dose in the range of 25 to 200 mg/day, depending on clinical efficacy and tolerability. Topiramate was discontinued after 10 days, while concomitant medication remained unchanged. After 5 days, topiramate was reintroduced at similar or increased dosages for another 7 days. Patients were assessed with the YMRS; the Clinical Global Impressions scale version for bipolar patients; and the 21-item Hamilton Rating Scale for Depression. RESULTS: Seven of the 11 patients initially showed a good antimanic response with > 50% reduction in YMRS score. One patient showed psychotic features following rapid increase in topiramate dosage and dropped out on day 10. After discontinuation of topiramate, 7 of the remaining 10 patients worsened (increase of > or = 25% in YMRS score), 2 remained stable, and 1 discontinued follow-up after good recovery. After reintroducing topiramate, all patients improved again within a week, with 8 of 9 meeting the responder criterion of > or = 50% YMRS score reduction when comparing baseline values with those of day 22. With the exception of the patient who developed psychosis, topiramate was well tolerated. Concomitant medication did not interfere with plasma levels of drug, except for carbamazepine level in 1 patient. CONCLUSION: The antimanic response among patients in this study appears reproducibly linked to the addition of topiramate.

Dysregulation of ion fluxes in bipolar affective disorder.

Bipolar disorder has attracted numerous research from different neurobiological angles. This review will summarize selected findings focusing on the role of disturbed transmem-braneous ion fluxes. Several mood stabilizers exhibit a distinct profile including effects on sodium, calcium and potassium conductance. In summary, some decisive mechanisms of action as calcium antagonism and modulation of potassium currents may play a crucial role in the success of any given mood stabilizer in bipolar disorder.

NMDA-dependent modulation of CA1 local circuit inhibition.

Whole-cell and extracellular recording techniques were used to examine local circuit inhibition in the CA1 region of the rat hippocampus in vitro. Activation, primarily of the recurrent inhibitory circuit by alvear stimulation, elicited an IPSP in pyramidal neurons that was dependent, in part, on NMDA receptor activation. Application of a tetanizing stimulus to the alveus evoked long-term potentiation (LTP) of the intracellularly recorded recurrent IPSPs. This LTP also was NMDA-dependent and was more sensitive to blockade by the NMDA antagonists 2-amino-5-phosphonovalerate (APV) and N-acetyl-aspartyl-glutamate, than the excitatory LTP produced by Schaffer collateral stimulation. With regard to APV, the sensitivity of inhibitory LTP was an order of magnitude greater. A biophysical simulation of hippocampal CA1 circuitry was used in a model of learned pattern recognition that included LTP in both excitatory and inhibitory recurrent circuits. In this model, selective blockade of inhibitory LTP produced aberrant spread of lateral excitation, resulting in confusion of normally distinguishable patterns of neuronal activity. Consideration is given to the possibility that selective disruption of NMDA-dependent modulation of local circuit inhibition may serve as a model for some aspects of dysfunction associated with NMDA-antagonist exposure and schizophrenia.

Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal.

Increased discharge activity of mesopontine cholinergic neurons participates in the production of electroencephalographic (EEG) arousal; such arousal diminishes as a function of the duration of prior wakefulness or of brain hyperthermia. Whole-cell and extracellular recordings in a brainstem slice show that mesopontine cholinergic neurons are under the tonic inhibitory control of endogenous adenosine, a neuromodulator released during brain metabolism. This inhibitory tone is mediated postsynaptically by an inwardly rectifying potassium conductance and by an inhibition of the hyperpolarization-activated current. These data provide a coupling mechanism linking neuronal control of EEG arousal with the effects of prior wakefulness, brain hyperthermia, and the use of the adenosine receptor blockers caffeine and theophylline.