Effects of artificial food colorings in children with hyperactive symptoms. A critical review and results of a controlled study.

The "Feingold diet," which eliminates artificial food colorings, has been claimed to be beneficial to hyperactive children. Previous studies have yielded equivocal results. We sought to maximize the likelihood of demonstrating behavioral effects of artificial food colorings by (1) studying only children who were already on the Feingold diet and who were reported by their parents to respond markedly to artificial food colorings, (2) attempting to exclude placebo responders, and (3) administering high dosages of coloring. The design was a double-blind crossover with randomized; 11 children maintained on the Feingold diet were challenged with food coloring and placebo (one each week). Evaluations by parents, teachers, and psychiatrists and psychological testing yielded no evidence of a food coloring effect.

Growth of hyperactive children on maintenance regimen of methylphenidate.

The growth in height and weight of 86 hyperactive children receiving methylphenidate hydrochloride (average, 40 mg/day for up to four years) was compared with general population norms on recently updated growth charts. A significant decrease in height percentile was apparent after 2, 3, and 4 years of treatment but not after one year. A significant loss in weight percentile occurred onward from the first year of treatment. Dosage was significantly associated with the decrease in height and weight percentile. Greater initial height and weight were associated with greater growth decrements. The use of adjunctive thioridazine hydrochloride (mean, 87 mg/day) did not influence the growth of children receiving methylphenidate. Although the magnitude of the growth suppressant effect in groups was small (dosage accounted for only 2% of the variance in final height), the results suggest that clinicians should monitor the growth of hyperactive children receiving stimulants and consider dosage reduction in individual cases should evidence of growth suppression occur.

Methylphenidate effects on symptoms of attention deficit disorder in adults.

The objectives of this study were (1) to determine whether attention deficit disorder (ADD) is a specific diagnostic entity in adulthood; (2) to evaluate, using a double-blind crossover design, the efficacy of methylphenidate hydrochloride in adults with evidence of residual ADD with hyperactivity (ADD-H) (N = 26); and (3) to evaluate the specificity of drug response by also administering methylphenidate to patients with similar adult symptoms but no childhood history of ADD-H (N = 35). Results indicated success in differentiating relatively distinct groups. However, no overall benefit from methylphenidate was evident, regardless of childhood history of ADD-H. Approximately 25% of the sample appeared clinically to benefit from methylphenidate, but no clear-cut predictors of drug response were identified; history of drug abuse (polydrug) appeared to be the best predictor. Even among the responders, benefit was generally not as marked nor as clinically valuable as in childhood ADD-H.

Methylphenidate and growth in hyperactive children. A controlled withdrawal study.

The effect of stimulants on growth has been controversial. Among hyperactive children receiving long-term methylphenidate hydrochloride treatment, we examined the effects of methylphenidate withdrawal on the growth of hyperactive children randomly assigned to be taken off, or remain on, the medication regimen over two consecutive summers. After one summer, no group difference in height was found, but weight was higher in the group that had been taken off methylphenidate therapy. In contrast, two summers of being off methylphenidate treatment had a significant positive effect on height but not on weight. The results document a linkage between exposure to methylphenidate and reduction in growth velocity. However, they do not address whether the medication has long-term effects on height.

Extended-release physostigmine in Alzheimer disease: a multicenter, double-blind, 12-week study with dose enrichment. Physostigmine Study Group.

BACKGROUND: The efficacy of extended-release physostigmine salicylate, an acetylcholinesterase inhibitor, was evaluated in 850 subjects with mild-to-moderate Alzheimer disease (AD) in a multicenter trial. METHODS: Subjects initially entered a dose-enrichment phase in which they received 1 week each of physostigmine salicylate, 24 mg/d and 30 mg/d, and daily placebo. Among the subjects who completed this phase, 35.9% responded to physostigmine treatment, whereas 62.4% were considered nonresponders, and 1.6% could not be evaluated because of missing data. After a 4-week placebo-washout phase, 176 responder subjects were randomized to receive their best dose of physostigmine or placebo in a 12-week double-blind phase. Primary efficacy measures included the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC+), and the Clinical Global Impression of Change (CGIC). RESULTS: In the intent-to-treat analysis of the double-blind phase, physostigmine-treated subjects scored -2.02 points better than placebo-treated subjects on the ADAS-Cog (F1,167 = 6.42 [P = .01]) and 0.33 points higher on the CIBIC+ (F1,150 = 5.68 [P = .02]). No significant improvement was observed on the CGIC or the secondary outcome measures. Nausea and vomiting were experienced by 47.0% of all physostigmine-treated subjects during the double-blind phase. CONCLUSIONS: Physostigmine demonstrated a statistically significant benefit compared with placebo on a clinical global rating of change and an objective test of cognitive function. Given the frequency of gastrointestinal side effects, the role of this agent in clinical use remains to be determined.

Ceruletide for schizophrenia: a double-blind study.

Ceruletide, an analog of cholecystokinin (CCK), has been reported to have neuroleptic-like activity in mice, and, in three open studies, to benefit schizophrenic patients. This study evaluated ceruletide in schizophrenia using a double-blind design. Subjects were 17 chronic schizophrenics with residual symptoms following stabilization with neuroleptics. Patients randomly received two injections, 1 week apart, of either ceruletide (0.6 microgram/kg im) or placebo, while continuing neuroleptics; this regimen was found helpful in earlier studies. Evaluation included ratings of 29 variables related to prognosis in schizophrenia (e.g., age, number of previous hospitalizations), regular BPRSs and SCL-90s, and psychiatrist, patient, and relative ratings of global improvement. Results showed few significant differences between ceruletide and placebo, with exceptions as likely to favor placebo as ceruletide. Among the patients on ceruletide, no predictors of benefit were found. Possible reasons for the negative results are discussed.

A placebo-controlled evaluation of vasopressin for ECT-induced memory impairment.

Vasopressin may be involved in normal memory functions and may alleviate certain memory impairments. In this study, the usefulness of vasopressin to relieve electroconvulsive therapy (ECT)-induced memory impairment was evaluated using a placebo-controlled, random assignment, double-blind design. Patients were 33 depressives receiving bilateral ECT. Vasopressin, in a nasal spray, was administered q.i.d. from the first through the fifth ECT. Extensive memory testing evaluated both retrograde and anterograde amnesia; ratings of depression and patient ratings of subjective memory complaints were also obtained. Results did not show statistically significant evidence of benefit from vasopressin, though a number of comparisons were in the predicted direction. The role of vasopressin in reducing memory impairment of various types remains to be elucidated.

Metoprolol for intermittent explosive disorder.

Metoprolol, a selective beta 1-adrenoreceptor blocker, was administered to two patients with intermittent explosive disorder who had not done well with previous medications, including propranolol and carbamazepine. Both patients improved dramatically, suggesting clinical and theoretical relevance.

A high-dose, double-blind study of ceruletide in the treatment of schizophrenia.

Ceruletide, a cholecystokinin analogue, has been reported to interact with dopamine in the CNS and to benefit schizophrenic individuals. The authors, using a double-blind design, a higher total dose, and a larger sample size than previous studies, found no evidence of benefit.

State-dependent learning in hyperactive children receiving methylphenidate.

State-dependent learning refers to a failure of learning mastered under one drug condition to be remembered when tested under another drug condition. Previous studies of state-dependent learning in hyperactive children receiving stimulants have yielded conflicting results. The authors systematically evaluated learning and transfer of learning in children who were or were not receiving methylphenidate and included several design features intended to optimize the likelihood of demonstrating state-dependent learning. They found no evidence of state-dependent learning. These results diminish concern regarding state-dependent effects in hyperactive children who are positive drug responders and who are clinically administered methylphenidate to control their hyperactivity.

Clozapine for refractory schizophrenia: an open study of 14 patients treated up to 2 years.

Clozapine is a novel antipsychotic agent that selectively blocks mesolimbic--rather than nigrostriatal--dopamine receptors, causes fewer extrapyramidal symptoms than do other neuroleptics, and has superior antipsychotic efficacy in some patients. However, clozapine also causes agranulocytosis more frequently than do other neuroleptics. The evidence documenting the superior benefits obtained with clozapine has primarily involved short-term (4-6 weeks) trials, and the systematic evaluation of long-term clozapine use has been limited. In this study, 14 patients with refractory chronic schizophrenia were treated openly with clozapine up to 2 years; 8 did substantially better when given clozapine than they had when given other neuroleptics. That finding suggests that clozapine may provide a useful addition to the therapeutic armamentarium for the long-term treatment of schizophrenia, despite the increased risks and the need for frequent blood tests.

Methylphenidate in mild depression: a double-blind controlled trial.

The literature on the use of stimulants in depression is reviewed, and a controlled study is described. Twenty mildly depressed outpatients with Hamilton Depression Rating Scale scores of 14-24 were entered into a double-blind crossover study with randomized order, comparing methylphenidate (up to 60 mg/day) and placebo. No antidepressant effect was found. A beneficial effect of stimulants in subgroups of depressed patients remains to be proven.

A family study of patients with temper outbursts.

To evaluate the heritability of a personality trait, "having temper outbursts," and of associated diagnoses, we obtained histories of first degree relatives on two groups: (1) patients with temper outbursts (N = 33), and (2) diverse psychiatric patients without temper outbursts (N = 12). Family interviews were conducted blind to patient (temper or not) status, using a modified version of the Family History RDC. Though Ns are relatively small, and results therefore require confirmation, the data indicate familial transmission of temper problems; an average of 18.2% of Group 1 relatives had temper problems, compared to 4.3% for Group 2. The trait of having temper outbursts was more strongly transmitted than were specific diagnoses (e.g. Intermittent Explosive Disorder, Antisocial Personality Disorder or Residual Attention Deficit Disorder) associated with temper outbursts. Patients with neurological conditions apparently related to their temper outbursts were less likely to have positive family histories.

Risperidone: how good is the evidence for efficacy?

This article reviews the published literature evaluating the efficacy of risperidone. The literature includes three multicenter, double-blind studies that compared risperidone, haloperidol, and placebo, as well as three comparisons of risperidone with a standard neuroleptic. Efficacy of risperidone is reported, but most studies involved chronically hospitalized patients who were relatively refractory; the response to standard neuroleptics was not robust. Also, the reported superiority of risperidone on negative symptoms may be artifactual, since standard neuroleptics, because of extrapyramidal symptoms, can mimic or exacerbate negative symptoms. Finally, risperidone may have an antidepressant effect. It is as yet unclear whether risperidone is as effective as standard neuroleptics for positive schizophrenia symptoms in neuroleptic-responsive patients.

A pilot study of combined trazodone and tryptophan in obsessive-compulsive disorder.

An open pilot trial of combined trazodone and tryptophan for 11 patients with Obsessive-Compulsive Disorder was conducted to test the hypothesis that increasing serotonin activity is therapeutic for this condition. Results were not encouraging; several patients tolerated the combination poorly, but even among patients completing 2 weeks' treatment benefit was marginal.

The dexamethasone suppression test as an indication of depression in patients with mental retardation.

The Dexamethasone Suppression Test (DST) was performed for three groups of institutionalized patients with mental retardation: (a) patients with symptoms of depression, (b) nondepressed patients with other problematic behavior (aggressiveness, self-injurious behavior, or withdrawal), and (c) control subjects with no behavioral or psychiatric symptoms. Results showed that depressed patients more frequently (though not significantly) had positive DSTs and significantly higher cortisol levels compared with the other two groups. Patients with other problematic behavior did not differ from control subjects. The DST may be particularly valuable in diagnosing depression in individuals with severe mental retardation, who are often nonverbal and unable to express depressive symptoms.