Jerome Costa

A Double-Blind, Placebo-Controlled Study of a CCK-B Receptor Antagonist, CI-988, in Patients With Generalized Anxiety Disorder

This multicenter, double-blind, placebo-controlled, parallel-group, randomized study assessed the efficacy, safety, and tolerability of a novel CCK-B antagonist CI-988 in the treatment of generalized anxiety disorder (GAD). Patients received placebo or CI-988 (300 mg/day, thrice daily) for 4 weeks. Patients with a primary diagnosis of GAD according to DSM-III-R criteria were randomized. The study design included a 1- to 2-week single-blind placebo baseline phase, followed by a 4-week double-blind treatment phase. Efficacy was measured weekly by Hamilton Rating Scale for Anxiety (HAM-A), Clinical Global Impressions of Severity and Change, UCLA-Multi Dimensional Anxiety Scale, and Hamilton Rating Scale for Depression. Patients were also evaluated to determine whether they met criteria for irritable bowel syndrome (IBS) at screening and were evaluated with a gastrointestinal visual analog scale at each visit. Eighty-eight patients were randomized to CI-988 (N = 45) and placebo (N = 43) at three centers. CI-988 did not demonstrate an anxiolytic effect superior to placebo in this clinical trial. There was no significant difference in mean change in HAM-A total between placebo (-7.73) and CI-988 (-8.64). However, a significant treatment-by-center interaction and a highly variable placebo response rate among the three centers limit the interpretation of the results. CI-988 did not have an effect on symptoms of IBS other than diarrhea, which worsened in patients with IBS. Other than a higher incidence of some gastrointestinal symptoms (diarrhea, dyspepsia, flatulence, and nausea), CI-988 was well tolerated. Results suggest that testing higher oral doses of CI-988 may be warranted.

An open trial of glycine as an adjunct to neuroleptics in chronic treatment-refractory schizophrenics.

We administered glycine in fixed dosages to six male chronic schizophrenic patients concurrently treated with thiothixene or fluphenazine. These patients met DSM-III-R criteria for schizophrenia and historically demonstrated a lack of response to neuroleptics. The open trial of glycine consisted of a 1-week baseline period of observation and a 5-week trial of glycine as an adjunct to their fixed-dose neuroleptic regimen. Patients were administered a solution of 5 g of glycine dissolved in 1 ounce of water (30 ml) three times a day (15 g/day) after meals. The Brief Psychiatric Rating Scale (BPRS) was performed at baseline and weekly thereafter. Baseline BPRS scores were compared with the final BPRS for each patient

High potency neuroleptics and violence in schizophrenics

In a controlled study, inpatient violence was measured during placebo, high-potency (haloperidol) and low-potency (chlorpromazine or clozapine) neuroleptics. Some patients had a marked increase in violent behavior with the moderately high-dose haloperidol, but not with low-potency neuroleptics. The authors discuss reasons for the increased violence with haloperidol, including akathisia and drug-induced behavioral toxicity.

Neuroleptic-induced hypothermia associated with amelioration of psychosis in schizophrenia

Body temperature is a regulatory function of the hypothalamus. Recently, DeMet et al. (Society for Neuroscience Abstracts Vol 12, 1986) reported that apomorphine stimulation of dopamine autoreceptors caused a significant decrease in metabolic rate in the posterior heat-conserving area of the hypothalamus. The logical hypothesis to follow is that apomorphine administration should induce a decrement in body temperature; this in fact was demonstrated by Cutler et al. (Commun Psychopharmacol 3:375-382, 1979) in humans. It is well known that neuroleptics also disrupt thermoregulation (Clark: Neurosci Biobehav Rev 3:179-231, 1979) and affect dopamine autoreceptors. Therefore, eight chronic treatment-resistant schizophrenics underwent a 6-week single-blind trial of haloperidol and then a subsequent 6-week double-blind trial of clozapine. Both haloperidol and clozapine significantly lowered oral body temperatures relative to baseline washout temperatures. More interestingly, clozapine relative to haloperidol was found to induce a greater decrement in body temperature and was associated with greater clinical improvement. Possible confounding variables are discussed, as is the possible neurochemical basis for the amelioration of psychosis associated with hypothermia.

Efficacy of Adjunctive Carbamazepine in the Treatment of Chronic Schizophrenia

Six treatment-resistant schizophrenic patients were given a ten-week single-blind trial of carbamazepine. Treatment resistance was determined on the basis of documented failure to respond to treatment with at least three neuroleptic drugs from two different chemical classes. The adjunctive use of carbamazepine resulted in a significant improvement of the negative symptoms of schizophrenia. These symptoms are often poorly responsive to conventional antipsychotic drugs. Therefore, controlled studies should be performed to further assess the possible efficacy of carbamazepine in schizophrenia.

Subjective neuroleptic response and treatment outcome under open and double-blind conditions — A preliminary report

1. A patients early subjective response to a neuroleptic was recorded in 17 schizophrenic patients following a fixed dose of neuroleptic under both open and double-blind placebo-controlled conditions. 2. High correlations were found between a patients subjective response at 2.5, 24 and 48 hours after the initial dose, suggesting that the timing of the initial subjective response rating is not critical. 3. The relationship between the psychiatric improvement and subjective response was not significant under double-blind conditions (r = 0.004), while the relationship under the open condition showed a trend towards significance comparable to earlier reports (r = 0.32). 4. The findings question the usefulness of applying early subjective response to a neuroleptic to predict clinical improvement.

Serum homovanillic acid concentrations in carbamazepine-treated chronic schizophrenics

Carbamazepine (CBZ) is clinically efficacious for the treatment of acute mania (Ballenger and Post 1980)) schizoaffective and schizophreniform disorders (Placidi et al. 1986), and excited psychotic states, including violent and aggressive schizophrenic patients (Hakola and Laulumaa 1982; Klein et al. 1984). However, there have been no well-controlled studies investigating the clinical efficacy of CBZ as the sole antipsychotic for the treatment of chronic schizophrenia. We report a preliminary, singleblind, 4-week trial of carbamazepine in a group of nonviolent chronic schizophrenic patients. In addition to the performance of routine clinical ratings, serum homovanillic acid (HVA) concentrations were measured to examine the presynaptic dopaminergic effects of CBZ.

Effects of carbamazepine on serum calcium in schizophrenia.

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