Psychotropic effects of carbamazepine in epilepsy: a double-blind comparison with phenytoin.

The "psychotropic" effects of carbamazepine were evaluated with phenytoin (Dilantin) as reference agent in a counterbalanced, crossover study. Forty adult epileptics were given a series of neuropsychologic tests and the MMPI after 4 months on each agent. Most abilities were much the same with either anticonvulsant, but there were fewer errors with carbamazepine on mental tasks requiring attention and problem solving, and some improvement in emotional status was suggested. The findings were consistent with patient reports of improvement in alertness and mental functioning. These results combine with the excellent anticonvulsant properties of carbamazepine to support its use as an anticonvulsant.     

A comparison of phenytoin and pheneturide in patients with epilepsy: a double-blind cross-over trial

A double-blind cross-over trial between pheneturide and phenytoin in ninety-four outpatients with epilepsy is described. There was no significant difference between the frequency of seizures in the two groups. The difficulties in comparing two anticonvulsants of similar efficacy are discussed particularly in relation to ethical problems, the selection of patients and trial design.     

A double-blind placebo-controlled crossover study of phenytoin in individuals with impulsive aggression.

The present study examines the behavioral and psychophysiological effects of phenytoin (PHT) in individuals who display impulsive-aggressive outbursts. In a double-blind placebo-controlled crossover design, individuals meeting previously established criteria for impulsive aggression were administered PHT and placebo during separate 6-week conditions. The efficacy measures used were the Overt Aggression Scale (OAS) and the Profile of Mood States (POMS). Psychophysiological measures (evoked potentials) were taken at baseline and at the end of each 6-week condition. Photic stimulation was used to evoke the mid-latency P1-N1-P2 waveform complex. Analysis indicated a significant decrease in the frequency of impulsive-aggressive outbursts during PHT administration compared to baseline and placebo. Analysis of the psychophysiological data showed significantly increased P1 amplitude and significantly longer N1 latency during PHT administration. In addition, a reduction in N1 amplitude during PHT administration was also suggested. These findings indicate reparation of physiological abnormalities previously observed in impulsive-aggressive individuals and imply more efficient sensory processing and effective orienting of attention. Taken together, these results provide insight as to the physiological mechanisms by which PHT serves to ameliorate impulsive-aggressive behavior.     

Controlled double-blind trial of phenytoin vs. fluoxetine in major depressive disorder

BACKGROUND: Phenytoin was the first non-sedative anticonvulsant introduced and is still the anticonvulsant most widely used worldwide in neurology. Given the efficacy of the anticonvulsant lamotrigine in the depressed phase of bipolar disorder, a critical theoretical question is whether other anticonvulsants used in treating bipolar disorder might be similarly effective. We therefore undertook a controlled trial of phenytoin versus fluoxetine in major depressive disorder. METHOD: Data were collected from July 2001 to July 2003. Thirty-three subjects entered the study. All patients met DSM-IV criteria for major depressive disorder and scored a minimum of 18 on the 24-item Hamilton Rating Scale for Depression (HAM-D) at baseline. After a 3-day washout of any previous medications, patients were randomly assigned to fluoxetine or phenytoin in identical capsules. Each capsule contained phenytoin 100 mg or fluoxetine 7 mg plus cornstarch. Patients started with 1 tablet daily and increased every other day until they were taking 1 tablet 3 times daily with meals. Blood phenytoin levels were taken after 1 week, 3 weeks, and 6 weeks, and dosage was adjusted to achieve blood levels of 10 to 20 microg/mL, to a maximum dose of 4 capsules per day or a minimum dose of 2 capsules per day. Fluoxetine patients were assigned dummy blood phenytoin levels by the control psychiatrist such that the treating physician would raise the number of capsules to at least 3 per day (20 mg of fluoxetine). RESULTS: Thirty-three patients entered the study, and 28 (N = 14 in each treatment group) completed at least 3 weeks and were included in the data analysis. Patients who dropped out after week 3 (3 patients) were included in the study as last value carried forward. There was no difference between treatment groups in overall rate of response or speed of response. CONCLUSION: The absence of a placebo arm in our study allows for the possibility that neither treatment was more effective than placebo. However, the exclusion of past fluoxetine nonresponders and the minimum HAM-D score at baseline of 18 make this possibility unlikely.     

Intramuscular lorazepam. A double-blind comparison with diazepam and placebo

In this double-blind, placebo-controlled study, 24 anxiety neurotic patients were randomly assigned equally into the intramuscular placebo, lorazepam or diazepam groups. The results indicated that lorazepam was as effective as diazepam in overall efficacy and was superior to diazepam in certain cluster scores including the Obsessive Compulsive Phobic Cluser of the Wittenborn Psychiatric Rating Scale.     

A double-blind study comparing carbamazepine with phenytoin as initial seizure therapy in adults

Carbamazepine was compared with phenytoin in a double-blind study. Of 87 patients, data on 70 patients were complete and used for analysis. Thirty-five patients were treated with each drug. The incidence of major side effects, minor side effects, and complete control (85%) was the same in both groups. A mild but significant elevation of WBC count was found before initiation of drug treatment in the patients presenting with generalized convulsive seizures. Sporadically, elevations in SGOT and LDH were seen; WBC counts below 4,000 were reported, but these were not clinically significant.     

Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine

The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics. DSM-III schizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 +/- 14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the double-blind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.     

Efficacy of fluvoxamine in obsessive-compulsive disorder. A double-blind comparison with placebo

A six- to eight-week double-blind placebo-controlled trial of the potent and selective serotonin reuptake inhibitor fluvoxamine was conducted in 42 patients with primary obsessive-compulsive disorder (OCD). Approximately one half of the patients also had symptoms of major depression. Fluvoxamine was significantly better than placebo on all measures of obsessive-compulsive symptoms. Nine of 21 patients were responders ("much improved") with fluvoxamine compared with no responders with placebo, and fluvoxamine was effective in patients with OCD both with and without secondary depression. Response of OCD was not correlated with severity of baseline depression. These data lend partial support to the serotonin hypothesis of OCD. However, since a number of patients failed to respond to fluvoxamine, the role of other neurochemical systems in this disorder needs to be explored.     

Gangliosides in the treatment of mental deterioration. A double-blind comparison with placebo.

Thirty patients showing signs of mental deterioration were submitted to a neuropsychological battery before and after treatment with gangliosides. Their performances were compared, in a double-blind study, with those obtained on the same tests by 30 patients affected by similar degrees of dementia and treated with placebo. The improvement shown on Raven's Coloured Progressive Matrices and on Immediate Visual Memory by the active group was significantly higher than that shown by the placebo group. Furthermore, an evaluation of the overall effect of gangliosides therapy showed a highly significant difference between the active and placebo group, still in favour of the subjects treated with gangliosides. It is concluded that gangliosides may exert a positive effect in the treatment of demential syndromes.     

A comparison of phenytoin and valproate in previously untreated adult epileptic patients.

Eighty-eight patients with the onset of epilepsy in adult life were randomly allocated to treatment with sodium valproate (600 mg/day), or phenytoin (300 mg/day), and followed up for at least 12 months. Both drugs were highly effective in the control of tonic-clonic seizures, irrespective of whether they were accompanied by focal features, but were markedly less effective in the control of partial seizures. Two patients exhibited acute allergic reactions to phenytoin. No significant differences have yet emerged in the efficacy of the two drugs, and valproate may be considered as a "fist-line" anticonvulsant in the treatment of adult onset epilepsy.     

Flunarizine, a new preventive approach to migraine. A double-blind comparison with placebo

Seventeen patients with common or classic migraine were prophylactically treated with 10 mg flunarizine daily, whereas 18 patients received a placebo during a 12-week randomized double-blind study. In the gross flunarizine was significantly superior to the placebo. Only 3 patients felt that flunarizine had been useless and the investigator also guessed the medication code correctly in all but these 3 cases. After a 1-month starting period the difference between flunarizine and placebo in reducing the frequency of the migraine attacks became statistically significant in favour of flunarizine. The mean monthly number of attacks was respectively 3.3 and 3.8 before the study and 1.4 and 3.2 during the study. The limited scale of the trial precluded a judgment as to whether one type of migraine would respond better to flunarizine than the other. Side-effects were negligible, weight gain being secondary to the therapeutic effect rather than an untoward consequence of treatment.     

Sertraline in obsessive-compulsive disorder: a double-blind comparison with placebo

Many agents that affect the brain's serotonergic system appear to be at least partially effective in the treatment of patients with obsessive-compulsive disorder. However, in this 10-week double-blind trial in which 10 patients received sertraline and nine received placebo, sertraline was ineffective according to four measures of obsessive-compulsive symptoms. The authors discuss the implications of these preliminary findings for the serotonergic theory of obsessive-compulsive disorder and the need to explore the role of other neurochemical systems in this disorder.     

Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin

In a randomized, nonblinded clinical trial, 36 consecutive patients with generalized convulsive status epilepticus were treated with either combination diazepam and phenytoin (DZ/DPH) or phenobarbital (PB). Phenytoin was added to the PB regimen if seizures persisted for 10 minutes after beginning therapy. The cumulative convulsion time (total time spent in active convulsive movements) was shorter for the PB group than for the DZ/DPH group (median, 5 versus 9 minutes, p less than 0.06); the response latency (elapsed time from initiation of therapy to the end of the last convulsion) was also shorter for the PB group (median, 5.5 versus 15 minutes, p less than 0.10). The median cumulative convulsion time is between 0 and 14 minutes shorter for the PB regimen than for the DZ/DPH regimen (95% confidence interval). Similarly, the median response latency for the PB regimen is between 1 minute longer and 20 minutes shorter than that for the DZ/DPH regimen (95% confidence interval). The frequencies of intubation, hypotension, and arrhythmias were similar in the two groups. Eleven of 18 patients in the PB group responded to phenobarbital monotherapy. We conclude that the PB regimen is rapidly effective, comparable in safety, and enjoys certain practical advantages in comparison with the DZ/DPH regimen.     

Intrathecal baclofen for intractable spinal spasticity--a double-blind cross-over comparison with placebo in 6 patients.

A group of six subjects with intractable spinal spasticity completed a double-blind cross-over paradigm in which they received two intrathecal bolus injections of baclofen solution five hours apart on two different days and two intrathecal bolus injections of placebo saline five hours apart on two other days. Each subject was repeatedly tested with a battery of clinical and physiological tests. In contrast to the placebo injections, the group responded to the baclofen injections with subjective and objective, clinically significant improvement in parameters of spasticity in their lower limbs, including muscle tone, frequency of spasms, hyperreflexia and passive range of joint motion. Furthermore, this improvement was maintained following thirty consecutive days of intrathecal bolus injections of baclofen at a fixed dose.     

Paroxetine versus placebo: a double-blind comparison in depressed patients.

BACKGROUND: Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI). The present study assessed the efficacy and tolerability of paroxetine against placebo in depressed outpatients. METHOD: A double-blind, parallel-group study was undertaken in four stand-alone centers. Patients aged 18-65 years, meeting DSM-III criteria for major depression, and having a Hamilton Rating Scale for Depression (HAM-D) score > or = 18 on the first 17 items of the HAM-D-21 were randomized to paroxetine or placebo for 6 weeks of treatment. Efficacy outcome variables included the HAM-D, the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impressions Scale (CGI), and the Covi Anxiety Scale. Tolerability was assessed by asking a non-leading question. Routine laboratory safety and vital sign data from all four centers were pooled. The primary analysis used the intention-to-treat sample and for efficacy variables the last-observation-carried-forward data set was employed. Statistical methods included one-way analysis of variance for parametric and Fisher exact test for nonparametric variables. RESULTS: Significant differences (p < or = .05) were found between paroxetine and placebo on the HAM-D and CGI by Week 2 and on all efficacy outcome variables by Week 4. Improvement on the HAM-D sleep factor occurred 2 weeks prior to that seen on the retardation factor. Similar results were obtained when an adequate treatment group (therapy for > or = 28 days) was considered. A full clinical response (CGI-severity of illness score 1 or 2) was seen in over 40% of subjects. Adverse events were more common for paroxetine compared with placebo (p < or = .01). Somnolence was twice more common than nervousness. Dropout due to adverse events was similar between therapies. Paroxetine had no clinically significant effect on laboratory safety data or vital signs. CONCLUSION: Paroxetine was an effective, well tolerated, and safe antidepressant. Side effects were typical of the SSRI class of drugs. Symptoms indicative of a nonalerting profile were more common than those associated with alerting effects.     

A double-blind comparison of thioridazine and chlorpromazine

Summary This study was an attempt to compare the therapeutic efficacy of thioridazine and chlorpromazine, to evaluate areas of discrete psychologic change as well as somatic toxic effects accompanying the therapeutic use of the two drugs, and to explore the relation between objectively and subjectively reported affects and behavior.There was no significant difference between the drug groups relative to clinical improvement, days on the drug, drug dosage or toxic side effects. Thus acute psychological disturbance (and especially acute schizophrenia) responds equally well to chlorpromazine and thioridazine.The data on the subjects in each group were considered for change over time, and the following significant differences were noted. In the first week of the drug period a decrease in anxiety and depression occurred with chlorpromazine. Both drugs decreased activity, schizophrenic excitement, and paranoid ideation after one week—while deactivation increased. Chlorpromazine reduced the intensity of hallucinations and improved attention and vigilance, while hyperactivity and ideas of persecution were lessened in the patients receiving thioridazine.Self-reported affectual improvement appeared to be unrelated to the study drug treatment. There was no correlation between toxic side effects and self- and other-reported behavioral change in the drug groups. Except for feelings of guilt-shame, self ratings and observer ratings of affects such as anxiety, aggression, helplessness-hopelessness, deactivation, activity and depression were independent.This research was supported by the department of psychiatry, University of Rochester School of Medicine and Dentistry.     

Delirium tremens: a double-blind comparison of diazepam and barbital treatment.

The effect of diazepam and barbital in the treatment of delirium tremens and other acute conditions related to alcohol abuse was evaluated in a double-blind trial. 91 patients participated in the study, 44 in the diazepam group, 47 in the barbital group. The choice of diazepam rather than chlordiazepoxide was motivated by its major anticonvulsive properties. Barbital was given by the oral route, diazepam as intramuscular injections. Different ways of drug administration to patients with delirium tremens are discussed. It is concluded that the two different ways used in the study probably did not have a noteworthy influence on the results. All patients were excluded who had taken psychoactive drugs before admission. Nevertheless a considerable part of the patients had diazepam, but not barbital, in the blood before treatment was initiated. This may give support to the use of barbital as a "special purpose drug" in the treatment of these conditions. The patients were divided into three diagnostic categories, according to the severity of the clinical condition. No difference between the two drugs tested was found in the milder conditions, but barbital was found superior to diazepam in the treatment of fully developed delirium tremens.     

Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind crossover comparison

Forty-eight children and adolescents with severe primary obsessive-compulsive disorder completed a 10-week double-blind crossover trial of clomipramine hydrochloride (mean dose [+/- SD], 150 +/- 53 mg/d) and desipramine hydrochloride (mean dose [+/- SD], 153 +/- 55 mg/d). Clomipramine was clearly superior to desipramine in significantly reducing obsessive-compulsive symptoms. Age at onset, duration and severity of illness, type of symptom, and plasma drug concentrations did not predict clinical response to clomipramine. Sixty-four percent of patients who received clomipramine as their first active treatment showed at least some sign of relapse during desipramine treatment. We further document the specificity of the antiobsessional effect of clomipramine and the need for maintenance treatment.