Neuroleptic trials

Importantly, they achieve this without inducing extrapyramidal side-effects or increasing prolactin secretion, which are real problems with neuroleptics. These results have been borne out by preliminary clinical trials of buspirone, used in combination with neuroleptics, and several novel S-HTja agonists (e.g. BSF 190555) are currently under development for this clinical application (Meltzer 1999). 

The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. 

In accordance with the structure of the BBB as a double Upid bilayer, classical neuroactive drugs such as benzodiazepines, neuroleptics and tricyclic antidepressive agents, are all small lipophilic molecules. These small molecular weight neuropharmaceuticals were selected by a trial and error approach because their structural characteristics allow for diffusion-mediated,... 

Most trials of the antipsychotic drugs are short term and consider only psychiatric outcomes. There is still a need for longer trials, and for the study of other variables such as patient and family quality of life and preference, or economic outcomes. Additionally, though newer neuroleptics and especially... 

Goff, D.C., Tsai, G., Levitt, J., Amico, E., Manoach, D., Schoenfeld, D.A., Hayden, D.L., McCarley, R., and Coyle, J.T (1999) A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 56 11-17. 

Buspirone was developed in the late 1960s with the intent of developing a better neuroleptic. Clinical trials demonstrated little antipsychotic effects however, animal models suggested some anxiolytic effects. The drug was marketed as an anxiolytic in 1986 (Cole and Yonkers, 1995 Baldessarini, 1996). 

Specific treatments guided by clinical, etiological (e.g., PANDAS), or genetic subtypes are the focus of ongoing efforts. Systematic augmentation trials using the atypical neuroleptics or the beta-blocker pindolol are needed. Family-based behavioral interventions are also under study. 

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. 

Tiapride and sulpiride are neuroleptics of the substituted benzamide class. These selective Dj blockers have weak antipsychotic properties and are not available in the United States, although they are commonly used in Europe for the treatment of tics. In a pair of 6-week controlled trials involving 27 children with TS, at doses ranging from 4 to 6 mg/kg/day, tiapride was superior to placebo and produced a 30%-44% decrease in videotaped tic counts (Eggers et ah, 1988). 

Turetz, M., Mozes, T, Toren, P., Chernauzan, N., Yoran-Hegesh, R., Mester, R., Wittenberg, N., Tyano, S., and Weizman, A. (1997) An open trial of clozapine in neuroleptic-resistant childhood-onset schizophrenia. Br J Psychiatry 170 507-510. 

Some of the earliest studies of psychotropic medications in preschool-age children involved neuroleptics. In autism, antipsychotics are the most frequently used psychoactive agents for the reduction of stereotypies, temper tantrums, aggressiveness against self or others, and hyperactivity (Campbell et al., 1999). There are seven studies with preschoolers with a total subject number of 59. Each of these seven studies involved medication trials with preschool children diagnosed with autism or childhood schizophrenia (Table 49.5). Only one study was a randomized, double-blind, pla-... 

Paradoxically, perhaps, DA antagonists have antidepressant properties (Robertson and Trimble 1982]. Controlled trials have established that some neuroleptics have antidepressant effects characterized by an early onset of action and relative lack of side effects. Furthermore, two drugs that are chemically related to the established neuroleptics loxapine and flupentixol and that retain substantial DA antagonism are marketed in various countries... 

The aforementioned study had insufficient power to determine whether patients with SRI-resistant OCD with comorbid schizotypal personality show a significant improvement after addition of neuroleptic. Despite the widespread clinical impression that neuroleptics are useful in treating OCD with psychotic symptoms, no controlled trials have been performed with this population. Further controlled studies with other SRls are needed to confirm the findings of McDougle et al. [1994] and to better define the appropriate target population for neuroleptic addition. The prescribing physician should be wary about exposing patients unnecessarily to the risks of chronic neuroleptic treatment. 

Utman RE, Su TP, Potter WZ, et al Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia comparison with the atypical neuroleptic, clozapine. Br J Psychiatry 168 571-579, 1996 Uttle A, Levy R, Chuaqui-Kidd P, et al A double-blind placebo-controlled trial of high-dose lecithin in Alzheimer s disease. J Neurol Neurosurg Psychiatry 12 110-118, 1985... 

Pimozide is FDA-labeled for Tourette s disorder and is particularly interesting in that it is a highly specific DA antagonist that may produce fewer adverse effects than haloperidol. In open studies with adequate doses, this agent has demonstrated efficacy for acute schizophrenia. Several double-blind trials comparing pimozide with other neuroleptics also found it to be an equally effective maintenance therapy ( 34, 35, 36, 37 and 38). We consider this agent to be as effective as the other standard agents, with the same, but perhaps less severe, side effects. 

More recently, some have advocated for adequate trials with at least one other novel agent and one neuroleptic before a trial with clozapine. 

Therapeutic Efficacy. The therapeutic efficacy of risperidone for schizophrenia has been well established in several controlled trials conducted worldwide ( 74, 75). The clinical efficacy trials performed to support approval of risperidone by regulatory agencies have all been published. Therefore, it is appropriate to combine these data using meta-analytic techniques to explore the efficacy of risperidone compared with neuroleptics. For most drugs, the relationship of dose and response is defined by the classic sigmoidal curve. Thus, as the dose (or plasma level) increases beyond a threshold and reaches the linear portion of the curve, response increases. Once the dose is high enough to produce maximal clinical response, the dose-response curve then levels off. 

Because a therapeutic window has been hypothesized to exist for neuroleptics, its existence for risperidone is a reasonable supposition. Indeed, evidence to support such a window was established in the North American Clinical Trial and the International Collaborative Study, both of which found doses of 4, 6, and 8 mg superior to higher or lower doses of risperidone. 

In 1996, Pilowsky and coworkers (111) found that olanzapine-treated patients showed significantly lower occupancy of striatal D 2 receptors compared with neuroleptic-treated patients. In support of the clinical trial data, PET studies have shown that 5-HT 2 and D2 receptor occupancies with olanzapine and clozapine are comparable, and that olanzapine should have a low propensity to evoke acute EPS (112). 

In general, lower doses (e.g., risperidone 2 to 6 mg/day olanzapine 5 to 20 mg/day) are preferable, usually sufficient, and help avoid toxicity. At these doses, results suggest that olanzapine has a substantially lower propensity than neuroleptics to evoke EPS, and perhaps TD. Indeed, early clinical trials were unable to distinguish olanzapine from placebo for EPS or akathisia. Further, there is some indication that doses of risperidone 10 mg may produce less improvement and more side effects than doses in the 4-8 mg dose range. 

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