Haloperidol Subject

Only two randomized, controlled trials have been completed, and neither provides anything like compelling data (Table 2.6). Chouinard and Albright (1997) conducted a unique evaluation of a subset of patients from a previously conducted clinical trial. Subjects were categorized and profiled at baseline and end point according to clinical severity, and a group of psychiatric nurses were asked to rate various aspects of likely outcome and quality of life to each profile (mild, moderate or severe symptoms). Health state utilities were then calculated risperidone was found to provide more than double the number of quality-adjusted life years compared with haloperidol. Csernansky and Okamoto (1999) conducted a rather more conventional trial, but included no economic analyses. However, they did find that the use of risperidone substantially reduced relapse rates compared with haloperidol—an outcome likely to have a positive impact on cost-effectiveness. 

The answer is c. (Hardman, pp 574—575.) Phencyclidine is a hallucinogenic compound with no opioid activity Its mechanism of action is amphetamine-like. A withdrawal syndrome has not been described for this drug in human subjects. In overdose, the treatment of choice for the psychotic activity is the antipsychotic drug haloperidol. 

In the process of developing the Stetter reaction in ionic liquids, Gree and coworkers applied their methodology to the synthesis of haloperidol (Scheme 25) [101], A variety of aromatic aldehydes react with methyl acrylate 160 when butyl-methylimidazolium tetrafluoroborate [bmim][BF ] is used as solvent. In the synthesis of haloperidol, electron-deficient aldehyde 153 was subjected to standard reaction conditions with 160 to provide 161 in good yield. 

Of the atypical antipsychotics, clozapine, olanzapine, and risperidone have been studied the most. Clozapine was used to treat 10 treatment refractory acutely manic patients and 15 schizomanic patients. Using reduction in the YMRS score as the outcome measure, 72% improved (non-rapid cycling, bipolar patients). Comparison of olanzapine (5-20 mg) with placebo showed significant reduction of the YMRS in 49% vs. 24% of subjects by 3 weeks, with significant change evident by the first week. In a trial comparing risperidone at 6 mg with haloperidol at 10 mg and low-dose lithium (800-1200 mg/day) efficacy was similar over the 28 days of the trial. 

Fluphenazine, a typical neuroleptic of the phenothi-azine class, has been less widely used for treatment of tics than haloperidol or pimozide. A controlled trial of haloperidol, fluphenazine, and trifluoperazine found comparable tic-reducing efficacy, but greater sedation and extrapyramidal side effects for haloperidol fluphenazine was the best tolerated (Borison et al., 1982). In an open-label trial with 21 subjects who had an unsatisfactory response to haloperidol, fluphenazine had a superior side effect profile to that of haloperidol in the dose range employed (mean dose of fluphenazine, 7 mg/day, range 2-15 mg/day) (Goetz et al., 1984). In this group selected for an unsatisfactory response to haloperidol, 11 of the 21 subjects (52%) had a better response to fluphenazine than haloperidol, 6 subjects had a comparable response, and 2 subjects preferred haloperidol. 

Cohen, I.L., Campbell, M., Posner, D., Small, A.D., Triebel, D., and Anderson, L.T. (1980) Behavioral effects of haloperidol in young autistic children an objective analysis using a within-subjects reversal design. / Am Acad Child Adolesc Psychiatry 19 665-677. 

EPS, extrapyramidal side effects HPD, haloperidol MLD, molindone N, total number of subjects in study , number of preschool-age children in study RCT, randomized, double-blind, controlled trial RISP, risperidone SE, side effect TFP, trifluperidol THX, thiothixene. 

Chlorpromazine and clozapine at low doses lead to an increase in slow (delta, theta) waves and a decrease in alpha activity in the pharmaco-EEG of healthy subjects. Findings regarding beta activity are less uniform. Rohloff et ul. (1992) reported on an increase in slow frequency components and a decrease of alpha and beta activity after 4.0 mg of haloperidol. Low doses of amisulpride (up to 50 mg) were reported to display an alertness-enhancing effect (Rosenzweig et ul., 2002). 

Approximately 50 subjects were randomized to each group. Open lithium or VPA treatment was also used. Those patients treated with risperidone or haloperidol had a substantially greater decrease from baseline YMS scores than those on placebo (i.e., 14 for risperidone and 13 for haloperidol versus 8 points for the placebo group (p=0.009). Further, 57% of the risperidone group achieved at least a 50% decrease from the YMS baseline score, compared with 38% in the placebo group. This study demonstrates that the addition of risperidone or haloperidol produced a better response than that achieved with a mood stabilizer alone. 

The time-course of the prolactin increase has been examined in 17 subjects whose prolactin concentrations rose during the first 6-9 days of treatment with haloperidol (473). The increase was followed by a plateau that persisted, with minor fluctuations, throughout the 18 days of observation. Patients whose prolactin concentrations increased above 77 ng/ml (n = 2) had hypothyroidism, and it is known that TRH (thyrotropin) stimulates the release of prolactin (474). 

Some patients who take clozapine take another neuroleptic drug, and the consequences of this practice in terms of prolactin have been studied in five patients (758). After the addition of haloperidol (4 mg/day) to clozapine the mean prolactin concentration increased from 9.7 ng/ml to 16 ng/ml at week 4 and 19 ng/ml at week 6. Each subject had an increase in the percentage of D2 receptor occupancy, and the group mean increased from 55% at baseline to 79% at week 4 the increased prolactin concentrations correlated with receptor occupancy. 

Both phencyclidine and ketamine bind with high affinity to a number of receptors in the brain, but it is now accepted that the primary target is the sigma-PCP receptor site located in the ion channel of the NMDA excitatory amino acid receptor complex. The precise function of this receptor in the brain is still the subject of debate. It is now known that there are two distinct sigma receptor sites in the mammalian brain (ctj and a2) which are not associated with the NMDA receptor complex. Haloperidol and the atypical neuroleptic remoxipride bind with high affinity to such sites, and it has been postulated that some typical and atypical neuroleptics may owe some of their pharmacological effects to their action on such receptors. 

Rammsayer, T. Gallhofer, B. 1995, Remoxipride versus haloperidol in healthy volunteers psychometric performance and subjective tolerance profiles, Int.Clin.Psychopharmacol., vol. 10, no. 1, pp. 31-37. 

As a comparison, haloperidol (Haldol) is generally considered to be among the most potent neuroleptics and the most likely to cause extra-pyramidal reactions. In a double-blind study of first-episode patients diagnosed with schizophrenia, the subjects were randomly assigned to take 1, 2, 3, or 5 mg/day (Kapur et al., 2000). If the patients did not respond to the lower doses, they were raised to the limit of 5 mg/day. These are relatively small doses. The recommended initial dose for moderate symptoms or geriatric or debilitated patients is 1-6 mg/day (Drug Facts and Comparisons, 2007). For severe or chronic patients, it is 6-15 mg/day, with higher doses for prompt control. 

A recent study involving primates has demonstrated that both the older and the atypical neuroleptics shrink brain tissue during routine clinical exposure. Dorph-Petersen et al. (2005), from the Department of Psychiatry at the University of Pittsburgh, subjected three groups of six macaque monkeys each to oral haloperidol (Haldol), olanzapine (Zyprexa),... 

Because of their neurotoxicity, neuroleptics probably worsen any brain disorder. A controlled experiment with rats subjected to traumatic brain injury demonstrated that chronic, high doses of risperidone or haloperidol were detrimental, causing persistent cognitive deficits (Kline et al., 2000). 

---