Clomipramine in obsessive-compulsive disorder.

The effects of clomipramine hydrochloride (CMI) versus placebo upon DSM-III-defined obsessive-compulsive disorder (OCD) were assessed in a 10-week double-blind multicenter trial and in a corresponding 1-year double-blind extension study. The NIMH global O-C scale, a 15-point ordinal severity scale, incorporating categorical features specific to OCD, was used to evaluate the severity of obsessive compulsive symptoms over the course of treatment, and a physician's rating of global therapeutic effect was used to assess overall change from baseline. In the core study, patients receiving placebo demonstrated minor and nonsystematic changes, whereas patients who received CMI had clinically and statistically significant reductions in the global severity of their disorder. Findings from the extension study were consistent with continuing efficacy for CMI, whereas corresponding data for patients receiving long-term placebo were difficult to interpret. Based upon shifts in categorical severity, symptoms for over half those patients who received CMI were rendered subclinical or within a range of normal functioning. In contast, less than 5% of patients receiving placebo had their symptoms reduced to a subclinical level. Generally, both treatments were well tolerated. Previous studies have indicated therapeutic potential for CMI in obsessive compulsive disorder. These findings confirm and extend previous observations.

Informed consent for neuroleptic therapy.

The author suggests that the frequency and severity of tardive dyskinesia in patients treated with neuroleptic drugs requires that informed consent be obtained from all patients receiving such treatment. The three basic conditions for obtaining informed consent are reviewed with discussion of some of the ethical problems encountered in the informed consent procedure. Most of these problems will be resolved if specific, written, informed consent is obtained from the patient, or his representative, within six weeks of initiating therapy, although in some cases questions may be raised about the very possibility of obtaining consent.

Confusional paranoid psychosis after withdrawal from sympathomimetic amines: two case reports.

Paranoid psychosis may result from intoxication with, or withdrawal from amphetamines. The authors describe two cases of paranoid confusional psychosis commencing 1 week after the patients' withdrawal from sympathomimetic amines. The pathophysiology for this unusual disorder may be agonist-induced dopamine receptor hypersensitivity.

Cognitive performance on the Alzheimer's Disease Assessment Scale: effect of education.

The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) is used to monitor disease progression and treatment efficacy in clinical trials of Alzheimer's 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.

High-dose pyridoxine in tardive dyskinesia.

The clinical similarities of tardive dyskinesia and 1-dopa intoxication lend support to the post-synaptic hypersensitivity hypothesis in tardive dyskinesia. Pyridoxine, a co-factor in the decarboxylation of dopa, reverses the movement disorder of l-dopa intoxication. Although early studies of pyridoxine in tardive dyskinesia have not been encouraging, the results of the present study suggest that high doses of pyridoxine may reduce the frequency and severity of involuntary movements in tardive dyskinesia.

Treatment schedule as a determinant of the development of tolerance to haloperidol.

Three groups of rats received haloperidol 0.5 mg/kg IP twice daily for 20 days, twice daily for 10 days, or every other day for 40 days. The rats in control groups received saline injections according to the same schedules as the experimental groups. During the chronic treatments, spontaneous motor activity was measured as an indicator of behavioral tolerance, and at the completion of treatments, limbic and striatal homovanillic acid (HVA) levels were determined in order to provide a biochemical indication of tolerance. Both of the haloperidol groups on twice-daily injection schedules exhibited a trend towards recovery of spontaneous motor activity during treatment, indicative of behavioral tolerance, as well as reduced HVA levels indicative of near complete biochemical tolerance. The group receiving haloperidol every other day exhibited a trend toward behavioral intolerance to haloperidol, along with elevated HVA levels that indicated a complete absence of tolerance. The suggested importance of treatment schedule rather than cumulative drug dosage in the development of tolerance to haloperidol may have significance to long-term side effects of chronic neuroleptic treatment such as tardive dyskinesia and clinical issues such as drug holidays.

The effect of bupropion on nicotine craving and withdrawal.

RATIONALE AND OBJECTIVES: Bupropion has demonstrated efficacy for smoking cessation. Given the importance of nicotine craving and withdrawal in the smoking cessation process, the current study examined the effects of bupropion on these parameters during smoking abstinence. METHODS: During a 2-day Baseline phase with ad lib smoking, 91 non-depressed smokers (who were not trying to quit permanently) were administered measures of nicotine craving, withdrawal symptoms, and timed measures of cognitive performance five times daily. Participants were then assigned randomly to a 14-day treatment regimen with bupropion 300 mg/day, bupropion 150 mg/day, or placebo. Thereafter, the above measures were re-administered during 3 days of abstinence on a closed research ward. RESULTS: Relative to placebo, 300 mg bupropion significantly reduced abstinence-associated increases in rated depression, difficulty concentrating, and irritability, and attenuated a decrease in positive affect. The results also suggested that bupropion might have a positive effect on performance measures during the withdrawal period. No effects were observed on craving, anxiety, restlessness, or hunger. The lack of findings on craving measures may be explained by a floor effect; except on the first day of abstinence, neither drug nor placebo groups showed much craving elevation during abstinence. CONCLUSIONS: Study results indicate that bupropion ameliorates some nicotine withdrawal symptoms.

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.

Psychosis in Parkinson's disease: diagnosis and treatment.

1. This article reviews the prevalence, diagnosis, pathophysiology and management of psychosis in Parkinson's disease. 2. Psychosis in Parkinson's 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 patient's 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.

Oxiracetam in the treatment of multi-infarct dementia.

1. Initial clinical trials in approximately 200 patients with dementias of diverse etiology suggested that oxiracetam, a structural analogue of the nootropic piracetam, was of some benefit in the treatment of cognitive dysfunction. 2. Because previous studies had not specifically examined the effects of oxiracetam upon dementias of vascular origin, the present study evaluated the therapeutic efficacy and safety of oxiracetam in the treatment of symptoms of multi-infarct dementia (MID) of mild to moderate severity. 3. Incremental doses of up to 1200 mg oxiracetam daily were tested in a dose-range finding design in a group of patients with clinically and neuropsychologically confirmed MID. 4. Based on improvement in global evaluations of clinical change, our analysis suggests that the drug may be of some benefit in MID.

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.

Mineral springs and spring fever. Lithium: fact and fantasy in psychopharmacology.

Lithium salts have been employed as medical treatment for more than two thousand years. The history of lithium in medicine reveals a strictly empiricist approach to its use which has resulted in its varying popularity as a therapeutic treatment over the past century. Much of the enthusiasm about the therapeutic use of lithium has been generated by faulty scientific process. This paper reviews the scientific errors which have surrounded the medical use of lithium in history, discusses the metaphorical use of medical terminology and the problem which is posed by the literal interpretation of such terms, and challenges the currently accepted point of view that lithium is a specific treatment for mania. The scientific errors which have resulted in the introduction of lithium as a treatment for mania are reviewed, and it is proposed that lithium treatment be viewed as the paradigm of modern psychopharmacology. The author suggests that the empiricist approach in biological psychiatry requires critical scrutiny in order to avoid tragic consequences, regarding the hazards both to patients arbittrarily exposed to lithium therapy, as well as to the scientific concept of disease as it is modified by those who wish to re-define disease, empirically, in terms of response to treatment.

Neuroleptic drugs: how to reduce the risk of tardive dyskinesia.

Prescribing neuroleptic drugs to control disruptive behavior in geriatric patients exposes them to the risk of tardive dyskinesia. Neuroleptics must be administered in the lowest effective dose for the shortest possible period, and should be given only for specific indications, usually psychotic disorders.

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)