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Recent anecdotal single case reports have suggested that the new antiepileptic drug gabapentin might be effective in the treatment of manic episodes and in the prophylaxis of bipolar disorder. In the present open trial, 14 patients with acute mania were treated for up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Six patients were treated with gabapentin as add-on medication and 8 patients were treated with a high dose of gabapentin alone. Gabapentin was both efficacious and safe when applied in combination with other drugs such as lithium and valproic acid. All patients in the add-on group and 4/8 patients on gabapentin monotherapy finished the 21 day protocol. Analysis of the scores of the Bech-Rafaelsen Mania Assessment Scale (BRMAS) of these patients showed that the mean BRMAS score declined from 37.7 to 7.8 on day 21 in the add-on group and from 27.8 to 9.0 in 4/8 patients finishing 21 days in the monotherapy group. It is suggested that gabapentin monotherapy might be useful in selected patients to treat modest but not severe manic states. In addition, gabapentin in conjunction with other effective mood stabilisers seems to be safe and efficacious in the treatment of severe mania.

1. There is increasing evidence that standard treatment of mania with lithium or neuroleptics fails in many subtypes of mania, e.g. dysphoric mania or rapid cycling, and new strategies are needed. 2. This single case report reports on possibilities and pitfalls in alternative attempts to tackle a severe manic syndrome successfully. 3. In this patient, lamotrigine and valproate, the latter only in an i.v. formulation, led to a relief from mania. 4. It is concluded that the success of this treatment may be due to a common underlying mechanism of action of these drugs, most likely on the level of ion channel regulation, and that further experience with alternative formulations of standard treatments such as valproate i.v. should be collected.

Actions of the new antiepileptic drug lamotrigine were characterised using whole cell patch clamp recordings from rat CA1 pyramidal cells in vitro. The results suggest that lamotrigine, besides its previously described effect on the fast sodium inward current and calcium currents, modulates the transient potassium outward current ID. This may be an effective mechanism to inhibit pathological excitation., (Copyright 1998 Elsevier Science B.V.)

An ideal model for in vitro research purposes of epilepsies should reflect the different clinical aspects of epileptic seizures, both in vivo and, as far as comparisons are possible, in vitro. It should induce long-term changes on a cellular level analogous to what is observed in epileptic patients, and should be triggered by varying endogenous physiological processes without additional exogenous drugs. These criteria are satisfied in the low magnesium model of epilepsy. Reducing Mg2+ below physiological concentrations or omitting it from artificial cerebrospinal fluid in vitro induces synchronized depolarization shifts in limbic-cortical networks which can be easily recorded extracellularly with a basic electrophysiological set up. These depolarization shifts resemble an increase of the calcium flux into the cell. Multiple depolarizing mechanisms such as NMDA receptor activation or prevention of presynaptic adenosine action converge onto this central pathway. It is hypothized that disturbed calcium homeosthasis is not only a characteristic of epilepsies, but also of affective disorders. Thus, the low magnesium model enables us to screen substances in vitro not only for antiepileptic, but also potential psychiatric use by testing them for calcium antagonistic properties.

1. The kava-pyrones kawain and dihydromethysticin are constituents of Piper methysticum which exert anticonvulsant, analgesic and anxiolytic properties. 2. In the present study the effect of these kava-pyrones were tested on field potential changes (fp) induced by omission of the extracellular Mg2+, recorded from the area CA1 and CA3 of the hippocampal slice preparation of guinea pigs. These fp are generated by an activation of NMDA receptors and voltage dependent calcium channels. 3. Kawain and dihydromethysticin reduced reversibly the frequency of occurrence of fp in a concentration range from 5 to 40 mumol/l and 10 to 40 mumol/l, respectively. 4. Reduction of the fp frequency after addition of subthreshold concentrations of 5 mumol/l kawain and 10 mumol/l dihydromethysticin indicated additive actions of both drugs. 5. Since the serotonin-1A agonist ipsapirone also exerts anxiolytic effects, subthreshold concentrations of kawain or dihydromethysticin were combined with a subthreshold concentration of ipsapirone in another set of experiments. Combining kawain and ipsapirone or dihydromethysticin and ipsapirone caused a reduction of the rate of fp to 0.76 and 0.81 of the baseline value, respectively. 6. The findings suggest that (i) single constituents of Piper methysticum may have additive actions, (ii) that the two components kawain and dihydromethysticin may enhance the effects of the anxiolytic serotonin-1A agonist ipsapirone and (iii) that activation of NMDA receptors and/or voltage dependent calcium channels may be involved in the elementary mechanism of action of some kava-pyrones.

1. The benefit of a combined treatment with the calcium antagonist nimodipine and lithium in a bipolar I disorder (currently manic, DSM IV 296.44, ICD 10 F 31.1) was explored and documented in a longitudinal single case study. 2. Nimodipine (270 mg/d) was added to lithium (900 mg/d), substituting for previously administered neuroleptics, in an up to then unsatisfactorily treated manic patient. 3. A clear-cut improvement in the patient's condition was achieved within a fortnight, and lasted over the continuation period of this drug regimen. This combined treatment was discontinued after eight weeks and lithium alone was then administered. Within three months another manic episode appeared. 4. Side-effects and changes of lithium blood levels were not observed during the combined treatment with nimodipine and lithium. 5. Further research on the benefits of adding a calcium antagonist, instead of neuroleptics, to lithium therapy for bipolar manic disorder patients who do not respond sufficiently to lithium is recommended. In addition, the benefits of a long term prophylaxis of nimodipine alone or in combination with lithium should be evaluated in those bipolar patients who still show a high relapse frequency on lithium alone.

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.

Beneficial effects of inflammatory events on certain psychiatric disorders, including depression, were reported sporadically by ancient Greek physicians, but have been described also in our times by a few psychiatrists during the past decades. During febrile inflammatory events, mediators of the immune system such as interleukin-1 can be detected in the brain and may act on their respective receptors which have also been demonstrated in the brain. Since cytokines such as interleukin-1 have been shown in animal studies to exert sedative behavioral effects, to be somnogenic, and to induce slow-wave sleep (SWS), we performed a pilot study to evaluate scientifically the anecdotically reported beneficial effects of inflammatory states on depressive disorders. Mood and sleep parameters were monitored in seven drug-free, severely depressed patients before, during, and after the administration of a single dose of endotoxin. All patients responded with a short pulse of increased synthesis of the cytokines tumor necrosis factor, interleukin-1, and interleukin-6 and elevated body temperature for several hours. During the night following endotoxin administration, rapid eye movement (REM) sleep was significantly suppressed, while changes in slow wave sleep were not significant. During the next day, all patients were in a significantly improved mood; however a rebound of REM sleep was observed in the second night after endotoxin administration and mood worsened again during the next days, indicating an only transient beneficial effect of the treatment.

Preclinical studies indicate that a disturbed intracellular calcium ion homeostasis is involved in the pathophysiology of affective disorders. Therefore some calcium antagonists were investigated, especially in the treatment of the manic syndrome. In the present study the calcium antagonist nimodipine was used in 10 out-patients with single or recurrent depressive episodes. As a result the mean HAMD scores changed from 26.5 to 9.9 after the individual nimodipine administration. These single case reports suggest an effective new therapy strategy for the treatment of affective dysregulations and give rise to controlled clinical studies with calcium antagonists.

Biperiden, 4 mg, an anticholinergic drug that is relatively selective for the M1 receptor subtype, and bornaprine, 4 mg, a nonselective M1 and M2 antagonist, were administered orally in a randomized, double-blind design to twelve healthy volunteers to investigate the effect on polysomnographically recorded sleep. Both drugs suppressed rapid eye movement (REM) sleep as reflected by an increase of REM latency and a decrease in the percentage of REM sleep period time with the effects of biperiden being more pronounced. No significant effect on slow wave sleep was observed. The results of this study support the hypothesis that both the M1 and the M2 receptor subtype are involved in the regulation of REM sleep in humans.

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.

Carbamazepine (CBZ) is known to have beneficial effects in the treatment of epilepsies and in the prophylaxis of affective disorders. Since increased transmembrane calcium fluxes and intracellular calcium concentrations play a key role in the generation of epilepsies and possibly also in the development of these psychiatric disorders the effects of CBZ on epileptic discharges (elicited by caffeine, penicillin and low Mg2+) in CA3 neurons of hippocampal slices were compared with those of the organic calcium antagonist verapamil and found to be almost the same.

Carbamazepine (CBZ) is used in neurology for the treatment of epilepsies and trigeminal neuralgia and in psychiatry for the prophylactic treatment of affective and schizoaffective psychoses. Since a common mechanism of epilepsies and affective psychoses might be increased intracellular calcium ion levels, CBZ action was analyzed in penicillin, caffeine and low Mg2+ induced model epilepsies which have been shown to be suppressed specifically by organic calcium antagonists. In CA3 and CA1 areas of hippocampal slice preparations of guinea pigs CBZ reduced paroxysmal depolarizations and extracellular field potentials (EFP) in a typical time and concentration dependent manner as it is known from calcium antagonists. Furthermore, subthreshold concentrations of the organic calcium antagonist verapamil intensified the action of CBZ. NMDA induced increases of the discharge rate of EFP were, however, unaffected by CBZ.

Apart from the eminent changes in the neurotransmitter systems of the central nervous system, a disturbance of the calcium ion concentration may be of significance in the pathophysiology of affective psychoses. The present paper deals with the contribution of calcium ions in the generation of affective psychoses and discusses the calcium antagonism as a new strategy in the treatment of the disease. The following topics will be described: 1. Disturbances of calcium metabolism in affective psychoses, 2. a comparison of lithium and carbamazepine effects, 3. clinical studies with organic calcium channel blockers in affective psychoses and 4. the role of calcium ions in affective psychoses.

Three adult schizophrenic patients without a previous history of epilepsy are reported who, during clozapine treatment, developed paroxysmal EEG patterns and generalized myoclonic jerks without alteration of consciousness. These seizures were phenomenologically identical to those occurring in juvenile myoclonic epilepsy and were classified as generalized epileptic seizures. We tentatively conclude that generalized myoclonic epileptic seizures may be induced by clozapine.

Three cases of diffuse malignant mesothelioma in which samples of pleural fluid showed an unusual cytologic picture are presented. Instead of cells of an obvious mesothelial type forming organized clusters, the smears were dominated by foamy macrophage-like cells, with or without certain nuclear features suggesting malignancy. It is suggested that these cells were derived from neoplastic mesothelial cells by a process of differentiation.