The development of study exit criteria for evaluating antimanic compounds.

BACKGROUND: There is increasing interest on the part of investigators and the public at large in finding ways to study and improve treatments for the seriously mentally ill without exposing such individuals to unnecessary risks. One group of particular interest in this regard are patients suffering from acute mania. We set out to define "exit" criteria or novel clinical endpoints that might help to assess the efficacy of antimanic compounds. We sought a method that would be safer, more economical, and less sensitive to nonspecific factors in the clinical environment while still allowing unambiguous assessment of efficacy. METHOD: From a pool of subjects being screened for or already participating in intervention studies, we retrospectively identified 76 admissions of patients with a manic or mixed episode according to DSM-IV. We fit a mixed-effects regression model to all available data obtained using the Bech-Rafaelsen Mania Scale from admission to day 28 of treatment. Using the estimated model coefficients, we obtained empirical Bayes (EB) estimates of each subject's trend coefficients based on (1) all available data and (2) data through day 11 of treatment for mania. RESULTS: We found a high correlation (r = .67) between EB estimates of final response at day 28 and actual day 28 scores on the Bech-Rafaelsen scale based on scores through day 11. When subjects were categorized as full, partial, or nonresponders according to their final Bech-Rafaelsen score, we were able to show that only 2 of the 23 predicted nonresponders became full responders, 27 of the 31 predicted full responders became full responders, and 16 of the 22 predicted partial responders became partial or full responders. CONCLUSION: We conclude on the basis of this chart review study that it should be possible to define exit criteria for trials assessing the efficacy of antimanic compounds on the basis of relatively short duration exposure to experimental treatment.

Rolipram in major depressive disorder: results of a double-blind comparative study with imipramine.

Rolipram improves signal transmission in central noradrenergic neurones at a pre- and postsynaptic level, and is thus a novel approach in antidepressant therapy. In order to prove efficacy, tolerance, and safety, several controlled studies are underway. Results of a randomized double-blind comparative trial versus imipramine involving 64 in-patients with Major Depressive Disorder (DSM III) in six independent centers will be presented and discussed. The chosen biometric model provided evidence that towards the end of the study imipramine was superior to Rolipram. The particular clinical relevance of this difference is discussed. As regards tolerance, nausea emerged as the typical side-effect of Rolipram, whereas imipramine precipitated mainly anticholinergic side-effects.

A study to assess the anticholinergic activity of rolipram in healthy elderly volunteers.

Rolipram is an antidepressant with a novel mechanism of action: enhanced noradrenaline (first messenger) synthesis and release, and inhibition of cAMP (second messenger) breakdown. This study was aimed at objectively assessing potential anticholinergic effects of rolipram in healthy elderly volunteers by measurement of saliva production and pupil size. Eight male volunteers between 67 and 77 years of age first received in a randomized manner either a single dose of 50 mg amitriptyline or a placebo control. After a minimum washout period of seven days, they then received a multiple dosing regimen of a) 0.75 mg and b) 1.5 mg rolipram given every eight hours over a 5-day period with a two day washout between a) and b). Whereas no changes at all in pupil size could be observed, amitripyline significantly reduced salivary flow. Rolipram however had no effect on saliva production after either single or repeated administration of 0.75 or 1.5 mg. The results are discussed in connection with pharmacokinetic parameters obtained in the study.

Can changes in eye-contacts predict therapeutic outcome in schizophrenic patients undergoing neuroleptic treatment? Results of a preliminary study.

The proportion of interview time spent in eye-contacts was studied before the onset of and during neuroleptic treatment in a group of 24 male schizophrenic patients. A significant increase in eye-contacts after 14 days distinguished responders to neuroleptic treatment, while a tendency towards the same effect distinguished patients treated with haloperidol from those treated with perazine. Only in the subgroup of responders was there a significant relationship between increase in eye-contacts and reduction of psychopathologic symptoms, regardless of whether these values were compared for the same treatment days or whether early changes in eye-contacts were compared with final outcome of treatment after 28 days. Since the patient subgroups were rather small, the results should still be considered preliminary. A prospective study including more parameters of visual interaction, a larger patient sample, and a longer observation period is required.

A case of perazine-induced enteritis--allergy or pseudoallergy?

Almost all adverse reactions to neuroleptic drugs in the gastro-intestinal system can be explained by their peripheral cholinergic blocking action with subsequent inhibition of intestinal tone and peristalsis. As a rare condition, severe diarrhoea due to enteritis may occur. A case with this complication is presented, the etiology and pathogenetic factors are discussed.

[Angiologic and prognostic evaluation of brain stem injuries. Clinical, doppler-sonographic and neuroradiological findings]. / Angiologische und prognostische Beurteilung von Hirnstamminsulten. Klinische, dopplersonographische und neuroradiologische Befunde.

Due to suspect vascular occlusion characterized by disorders of brainstem function 183 patients were investigated using Doppler sonography of the vertebrobasilary vascular system. Extracranial vascular lesions were diagnosed in 32 patients (basilary steal syndrome, vertebral artery branching stenosis), 11 patients showed bilateral vertebral artery occlusion or basilary thrombosis, nine unilateral intracranial vertebral artery occlusion and 131 patients showed no abnormal findings. The prognostically worse intracranial lesions were all confirmed by angiography. Twenty-five patients with normal Doppler findings were also controlled. Of these, three patients showed macroangiopathy presenting as megadolichobasilary artery and haemodynamically ineffective stenosis of the basilary artery (one patient). In the majority of cases neurological disorders associated with normal Doppler sonography findings were however considered as representative of cerebral microangiopathy, characterized by a favourable prognosis.

Anterior interosseous nerve syndrome following supracondylar lesions of the median nerve: clinical findings and electrophysiological investigations.

Lesions at the volar aspect of the forearm may lead to isolated paralysis of the anterior interosseous nerve, which is a purely motor branch of the median nerve. The same syndrome may result from circumscribed damage at the level of the upper arm. Two patients are reported with the typical anterior interosseous nerve syndrome following supracondylar lesions of the median nerve and the literature is reviewed. In most cases this syndrome is a complication of supracondylar fractures of the humerus in children. A simple clinical test for the diagnosis, the pinch test, and the typical electromyographic findings are described. Whereas electroneurography has been considered to provide little help in diagnosis, a significantly lower nerve conduction velocity was found in the median nerve between the medial intermuscular spatium and the cubital fossa compared to the normal arm, and a prolonged response latency of the pronator quadratus of the injured arm following stimulation of the median nerve in the intermuscular medial spatium and the cubital fossa.