Joseph DeVeaugh-Geiss

Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder―a multicenter trial

Children and adolescents with obsessive compulsive disorder were studied in an 8-week, multicenter, double-blind, parallel groups trial of clomipramine hydrochloride (CMI) versus placebo. Efficacy assessments included the child version of the Yale-Brown Obsessive Compulsive Scale and the National Institute of Mental Health Global rating scale. At the end of 8 weeks, CMI-treated patients showed a mean reduction in Yale-Brown Obsessive Compulsive Scale score of 37% compared to 8% in the placebo group. Side effects were typical of tricyclic antidepressants. In a 1-year open label treatment, CMI continued to be effective and well tolerated.

Tardive Tourette syndrome

To the Editor: The report by Klawans and associates’ of Gilles de la Tourette syndrome induced by chlorpromazine was both enlightening and clinically useful, as I had seen a similar patient whose movement disorder did not follow a typical pattern, and who presented a diagnostic puzzle. This 65-year-old man, who had neither personal nor family history of neurologic disease, received neuroleptic drug therapy for 6 years (thioridazine 100 mg daily for 4 years, and perphenazine 4 to 12 mg daily for 2 years). During the course of this treatment he experienced extrapyramidal side effects, including tremor and cogwheel rigidity, which were left untreated and did not subside unless neuroleptic drugs were stopped. During the fourth year of neuroleptic therapy, he developed more severe parkinsonian signs with gait disturbance and involuntary movements of his head, neck, mouth, and extremities. The diagnosis of tardive dyskinesia was made; an attempt to discontinue neuroleptic drugs was unsuccessful, as this resulted in regression of his mental state, urinary incontinence, confusion, and severe motor restlessness. The treating physician referred this patient to me, and a gradual reduction of the neuroleptic dose was undertaken. Some increase in dyskinetic movements was observed with each 2-mg dose reduction. With this method of gradual withdrawal, there was no significant psychic disturbance, and we were able to reduce the perphenazine dosage from 12 mg daily to zero within a period of 10 months. Following this elimination of neuroleptic drug, the patient’s tardive dyskinesia, characterized by typical orofacial involuntary movements and choreiform movements of upper and lower extremities, remained stable for about 2 months and subsequently resolved very gradually, only to be replaced by grunting and barking vocalizations and very distinct tic-like movements in the orofacial region. These movements persisted for 4 months unchanged with no medication, and gradually disappeared over the next 2 months. Prior to the publication of the report of Klawans and associates, I did not know what to call this phenomenon, but now realize that this was probably a neuroleptic-induced dopamine hypersensitivity similar to the tardive dyskinesia which it replaced. Although Klawans and colleagues have reported the first case of “tardive Tourette syndrome,” this may be the first report of the evolution of this syndrome from a more typical tardive dyskinesia. Furthermore, the reversibility of this man’s movement disorder makes this case unusual. Although these reports may have clinical significance for physicians attempting to diagnose movement disorders in patients with histories of neuroleptic drug treatment, it seems to me that a more important issue may be raised by these observations. Haloperidol, one of the most potent of the neuroleptic drugs now marketed, is considered to be the treatment of choice in Gilles de la Tourette syndrome,2 and is widely used in Huntington d i~ease ,~ both disorders presumably representing a disturbance in dopaminergic systems. Considering the phenomenologic similarity of the movement disorders of tardive dyskinesia and Huntington disease, and the fact that neuroleptic drugs are clearly implicated in the etiology of tardive dyskinesia, it is reasonable to assume the possibility that patients with Huntington disease may be made worse in the long run by neuroleptic treatment. This speculation has been made previously,l and the recognition that neuroleptic drugs should not be given to patients with tardive dyskinesia is a reflection of this logical assumption. With the more recent description of a neurolepticinduced movement disorder resembling Tourette syndrome, a similar concern might be raised in the treatment of patients with idiopathic Tourette syndrome. There a re certainly many confusing and paradoxical aspects of neuropsychopharmacology, not the least of which is that a drug which is useful in alleviating symptoms of a disorder may also cause that disorder, and there is much that remains to be understood about neurophysiology before rational, effective, and safe treatments are available. Further research is necessary to solve these problems. In the meantime, it would seem that a prudent early approach to management of disorders such as Huntington disease and Tourette syndrome would be a conservative one that reduces the likelihood of an iatrogenic disorder being superimposed on the preexisting one, and that reserves the use of neuroleptic drugs for the more severely disabling conditions which would justify the risk.

Cognitive performance on the Alzheimer's disease assessment scale : effect of education

The cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-Cog) is used to monitor disease progression and treatment efficacy in clinical trials of Alzheimers disease (AD). Using data from a 12-week drug trial, we retrospectively studied the effect of education on ADAS-Cog performance in a group of 444 patients with AD. The effect of education was statistically significant on baseline ADAS-Cog total scores. This effect remained statistically significant after controlling for age, gender, and dementia severity. Education effects were also statistically significant at week 12 for ADAS-Cog total and 10 of 11 subitem scores in 138 AD patients in the placebo arm of the trial. Post hoc analysis showed that non-high school graduates performed worse than those with greater educational levels across a broad range of cognitive domains. Our results, in conjunction with reports linking lower educational level with a higher risk for AD, suggest that educational level of patients be given consideration in the design and interpretation of cognitive tests in AD drug trials.

GW320659 for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children

OBJECTIVE To assess the safety, tolerability, and efficacy of GW320659, a chemically novel inhibitor of norepinephrine and dopamine reuptake, in pediatric attention-deficit/hyperactivity disorder (ADHD). METHOD This was a multicenter, open-label, dose-titration study of seven daily dose levels of GW320659: 1.25, 2.5, 5, 7.5,10,12.5, and 15 mg. Treatment began with the lowest dose of GW320659 and increased weekly until subjects (mean age 9.1 years) achieved a maximum acceptable dose. Subjects remained at their maximum acceptable dose for a 4-week treatment period. The key efficacy end-point was clinical response (Clinical Global Impressions of Improvement score of 1 or 2 and an improvement of 5 or more points on at least one of the Conners Parent or Teacher Rating Scales Tscore). Other end-points included assessments of safety and of quality of life using the Child Health Questionnaire Parent Form 28 (CHQ-PF28). RESULTS Fifty-one subjects entered the titration phase and 46 subjects completed the study. During the treatment phase, these 46 subjects received a mean dose of 14.2 mg/day and the maximum exposure to GW320659 was 11 weeks. At the end of the treatment period, 76% of subjects showed improvement with GW320659 and there were significant improvements in 7 of the 12 subscales of the CHQ-PF28 compared with baseline (p < .05). Adverse events were generally mild; only five subjects required downward titration because of adverse events (three psychiatric, one neurological and urological, one cardiovascular), and no subject withdrew because of adverse events. CONCLUSIONS GW320659 may have clinically relevant efficacy in pediatric ADHD and was well tolerated in this short-term initial study in children.

NSAIDs and cognition in Alzheimer's disease

To the Editor: Recent studies have suggested a neuroprotective influence for nonsteroidal anti-inflammatory drugs (NSAIDs). [1-4] The Rotterdam Study, [1] the Canadian Study of Health and Aging, [2] and a co-twin control study [3] found that anti-inflammatory treatments were associated with a reduced risk of Alzheimers disease (AD). The Honolulu Heart Program study found that concurrent aspirin use was associated with superior cognitive scores in nondemented subjects. [4] We studied 444 AD subjects selected for a multicenter clinical trial to test the hypothesis that concurrent NSAID …

Psychosis in parkinson's disease: Diagnosis and treatment

1. This article reviews the prevalence, diagnosis, pathophysiology and management of psychosis in Parkinsons disease. 2. Psychosis in Parkinsons disease has been associated with all antiparkinsonian medications. The most common symptoms are vivid disturbing dreams, visual hallucinations and paranoid delusions. 3. The emergence of psychosis reduces the patients functional capacity and increases caregiver burden. It also poses a therapeutic dilemma because effective treatment of psychotic symptoms may result in worsening of motor symptoms and vice versa. 4. Increased physician awareness is essential for proper diagnosis and management. Withdrawal of anticholinergic medications and amantadine followed by levodopa dose adjustment is effective in many patients. 5. Atypical neuroleptics, in low doses, may be successful when other measures have failed. However, these agents are not approved for treating Parkinsonian psychosis and must be considered as investigational therapies.

The antiobsessional effects of clomipramine do not require concomitant affective disorder

Two multicenter double-blind trials of clomipramine (CMI) vs. placebo were carried out in patients with DSM-III defined obsessive-compulsive disorder (OCD). Study entry criteria were similar, but the trials differed in their permitted initial degree of affective disturbance. Subgroups of patients with primary OCD and no mood disturbance were identified in both trials. Analyses of findings from both trials were essentially equivalent and were consistent with significant antiobsessional effects of CMI but not placebo in nondepressed patients with primary OCD. Further comparisons with subgroups with concomitant affective disturbance did not demonstrate marked differences in outcome.

Pharmacologic Therapy of Obsessive Compulsive Disorder

OCD is an anxiety disorder that was once viewed as rare and very difficult to treat. Although the first evidence that a serotonergic drug, clomipramine, might be effective in treating symptoms of OCD was published by Fernandez-Cordoba and Lopez-Ibor Alino in 1967, controlled trials demonstrating the efficacy of pharmacologic treatments in OCD did not appear until the 1980s. The availability of potentially effective treatments, combined with the awareness of prevalence rates for the disorder that are higher than previously believed, led to considerable interest in OCD. Numerous studies have been undertaken to investigate the biology of OCD. The observation that drugs that act by inhibiting serotonin uptake, such as clomipramine, fluvoxamine, sertraline, and fluoxetine, are effective in treating symptoms of OCD has resulted in intense interest in the relationship between serotonin and this disorder. Several lines of investigation support a serotonergic hypothesis for the pathophysiology and treatment of this disorder. Clomipramine, a tricyclic antidepressant that is a potent serotonin uptake inhibitor, was the first pharmacologic treatment for OCD to be studied in large multicenter trials. The successful outcome of these studies resulted in marketing approval by the United States Food and Drug Administration in 1989. Subsequently, similar multicenter trials have been undertaken with the selective serotonin uptake inhibitors fluvoxamine, sertraline, and fluoxetine. Results from these multicenter trials indicate that all these drugs are more effective than placebo in treating OCD. However, meta-analytic techniques applied to the data from controlled trials of these drugs suggest that the effect size for clomipramine is somewhat larger than that of the selective serotonin uptake inhibitors. A number of other drugs that affect serotonin through mechanisms other than uptake inhibition have been tried as treatments for OCD. Because of the small size of many of these studies, it is difficult to evaluate them in the context of the multicenter trials that studied hundreds of patients. Nevertheless, there may be a role for other serotonergic drugs in the treatment of OCD, particularly as adjunctive treatments used to enhance the effect of the serotonin uptake inhibitors. The data supporting the use of adjunctive treatment are limited and cannot be considered to demonstrate definitively the value of augmentation strategies with adjunctive treatment. Nevertheless, the serotonin uptake inhibitors, although effective in a large number of patients, do not appear to provide adequate symptom relief for some patients. Furthermore, among the patients who do respond to serotonin uptake inhibitors, complete remission in uncommon, which leaves a need for improvement of therapies.(ABSTRACT TRUNCATED AT 400 WORDS)