Sulpiride

The primary action of the traditional neuroleptics, such as the phenothiazines and haloperidol, is blockade of D^sub 2^ dopamine receptors. The newer, so-called, atypical neuroleptics-such as clozapine, risperidone, quetiapine, and olanzapine-not only block dopamine receptors, but also are potent antagonists of one or more serotonin (5-hydroxytryptamine or 5-HT) receptors as well. Although there is some evidence that 5-HT blockade (particularly the 5-HT^sub 2^ receptor) may contribute to the antipsychotic effect of these agents, this action probably accounts for the lower risk of extrapyramidal symptoms (Huttunen, 1995). In a previous paper we reviewed the use of traditional neuroleptics in children and adolescents (Scahill & Skrypec, 1997). This paper describes the salient characteristics of the new combined 5-HT^sub 2^-D^sub 2^ antagonists and reviews the available data concerning their use in children and adolescents.

Atypical Neuroleptics

The term "atypical neuroleptic" describes a group of antipsychotic agents that may share some, but not all, pharmacological properties. Indeed, there is ongoing debate about precisely which features define this newer group of neuroleptics. Despite the lack of consensus, however, several pharmacological characteristics are generally considered essential. These include beneficial effects on the negative symptoms of schizophrenia (see Table 1), minimal elevation of prolactin levels, and reduced risk for extrapyramidal side effects (e.g., akathisia, Parkinsonism, or dystonia). Moreover, because the brain pathways associated with extrapyramidal side effects (EPS) have also been implicated in movement disorders, the atypical agents are presumed to be less likely to produce tardive dyskinesia.

The Dopamine Hypothesis of Schizophrenia

The clinical observation that dopamine-blocking medications can be effective in the treatment of psychosis promoted the widely held opinion that dopamine is a central player in the etiology of schizophrenia. However, the dopamine hypothesis is almost certainly incomplete. For example, a significant minority of patients with schizophrenia do not respond to traditional D2 blocking medications. Also, even when effective for the positive symptoms of schizophrenia, the D^sub 2^ blocking agents such as haloperidol, thiothixene, or thioridazine typically do not improve the negative symptoms of schizophrenia. These observations suggest that different mechanisms underlie positive and negative symptoms.

Negative symptoms, which are often referred to as "deficit symptoms," are believed to be caused by diminished activity of the prefrontal cortex. This view is supported by neuroimaging studies, which have shown reduced metabolic activity, as measured by cerebral glucose utilization, in dopamine-enriched regions of the prefrontal cortex among schizophrenic patients (Tamminga et al., 1992). Moreover, this reduced metabolic activity is associated with greater negative symptoms. A more recent positron emission tomography (PET) study by Dolan and associates (Dolan, Fletcher, Frith, Friston, Frackowiak, & Grasby, 1995) provides additional evidence for a functional deficit in prefrontal cortex. Compared to control subjects, adults with schizophrenia showed an enhanced response to the dopamine agonist, apomorphine, during a cognitive task. The difference between the groups was especially prominent in the anterior cingulate, which influences prefrontal function. The cingulate is a central component of the limbic system, which plays a role in attention and in the regulation of emotions and anxiety.

These observations are consistent with the functional organization of brain pathways proposed by Alexander, DeLong, and Strick (1986). In this conceptual framework, cortical-thalamic pathways are organized into five parallel circuits, each of which serves a separate function. Table 2 presents a brief outline of the three circuits that are presumed to play a role in the pathogenesis of schizophrenia.

Findings from animal studies imply that prefrontal cortex exerts regulatory control over subcortical structures such as the caudate. Thus, it may be that the underactivity of the prefrontal cortex results in a loss of inhibitory control of subcortical dopaminergic structures leading to their overactivity. This overactivity of subcortical structures could, in turn, lead to the emergence of positive symptoms, perhaps through stimulation of limbic structures such as the anterior cingulate (Deutch, 1992; Dolan et al., 1995). Through dopamine blockade in these overactive subcortical structures, traditional neuroleptics provide some relief for the positive symptoms of schizophrenia. However, because they do not enhance prefrontal function, the traditional neuroleptics do not improve the negative symptoms. EPS, such as akathisia, dystonia, and Parkinsonism, are presumed to be mediated by the motor circuit through the substantia nigra and represent unintended consequences of D^sub 2^ blockade (Deutch, 1994; Keltner & Folks, 1996).

Clozapine

The limitations of the traditional neuroleptics have prompted the search for better alternatives for the treatment of schizophrenia. This effort has proceeded along two lines: more specific agents (such as the selective D2 antagonist, sulpiride) and the combined 5-HT^sub 2^-D^sub 2^ antagonists. A description of the more selective agents such as sulpiride is beyond the scope of this paper. The prototype for the combined 5-HT^sub 2^-D^sub 2^ antagonists is clozapine and, until recently, it was the only available agent of this class. Over the past few years, however, several newer agents with this dual action have been released or are about to be released to the marketplace. One important difference between these compounds is the relative potency of the 5-HT^sub 2^ to D^sub 2^ blocking effects (Bymaster et al.,1996; Seeger et al.,1995).

Following its introduction in the 1960s, clozapine was nearly withdrawn from use due to concerns about agranulocytosis. Clozapine is reserved for cases of treatment-refractory schizophrenia. To date, only a few studies have evaluated the safety and efficacy of clozapine in pediatric populations (Frazier et al., 1994; Remschmidt, Schulz, & Martin, 1994). Collectively, these open-label studies treated 47 adolescents with schizophrenia (age range 12-18 years) and 70% (n = 33) of the combined sample reportedly had a positive response. The doses ranged from 50 - 825 mg per day; the most common side effects included sedation, weight gain, and hypersalivation. Eight of the 47 subjects in these studies had to discontinue treatment with clozapine due to seizure (n = 1), hypertension and tachycardia with ECG abnormalities (n = 2), leukopenia without agranulocytosis (n = 2), elevated liver function tests (n = 1), significant weight gain (n = 1), and severe sedation (n = 1).

More recently, the efficacy of clozapine was compared to haloperidol in 21 treatment-refractory adolescents with childhood-onset schizophrenia (mean age of 14.0 +/2.3 years at baseline) (Kumra et al., 1996). The 10 patients randomized to clozapine received an average daily dose of 176 ( +/- 149) mg compared with 16 ( +/- 8) mg for haloperidol. Clozapine was superior to haloperidol for both positive and negative symptoms. However, clozapine also was associated with a range of adverse effects including drowsiness, drop in neutrophil count in 5 patients, and seizures in 1 subject. Clozapine also was associated with significant elevation in hepatic enzymes in 1 subject.

Risperidone

Risperidone is a new neuroleptic medication that blocks D^sub 2^ receptors and 5-HT^sub 2^ receptors as well. The dual action is similar to clozapine and appears to be protective against extrapyramidal side effects (Leysen, Megens, Janssen, & Schotte, 1994). Although risperidone has pharmacological features in common with clozapine, it is a potent blocker at both D2 and 5-HT2 receptors. By contrast, clozapine is many times more potent at the 5 -HT^sub 2^ site than the D^sub 2^ site, where it is only a weak antagonist (Bymaster et al., 1996; Seeger et al., 1995). Table 3 summarizes the relative 5HT2 and D2 antagonism for the currently marketed or soon-to-be available atypical neuroleptics. Compared to clozapine, risperidone has slightly higher EPS liability, but it has not been associated with agranulocytosis.

Risperidone has been studied in several large multisite trials in adults with schizophrenia and appears to be safe and effective for the treatment of psychosis, with fewer side effects than haloperidol (Marder & Meibach, 1994). However, the data supporting its use in children and adolescents are limited.

In an open study of 7 children between the ages of 10 and 17, Lombroso and colleagues (1995) found that risperidone was effective in reducing tics in 5 of 7 patients. The drug was initiated at 0.5 mg per day and increased by 0.5 mg every 5-7 days over a 2-week period to a range of 1-3.5 mg per day in two divided doses. It was well-tolerated, with increased appetite and weight gain being the most commonly observed side effects.

Five other open trials with risperidone in pediatric populations have been published recently (Armenteros, Whitaker, Welikson, Stedge, & Gorman, 1997; Fisman & Steele, 1996; Mandoki, 1995; McDougle et al., 1997; Simeon, Carrey, Wiggins, Millin, & Hosenbocus, 1995). These five studies reported on a total of 49 children and adolescents (age range 7-18 years) with a variety of disorders including schizophrenia, psychotic depression, obsessive-compulsive disorder, pervasive developmental disorder, and severe attention deficit hyperactivity disorder. Although many of these patients had a positive clinical response, side effects including EPS were observed. For example, in the study by Armenteros et al., 6 of 10 adolescents with schizophrenia achieved a clinically significant improvement. Adverse effects in these 10 subjects included dystonia (n = 2), Parkinsonism (n = 3), drowsiness (n = 13), and weight gain (n = 4).

In summary, the dosing schedules used in these studies were not the same, and a careful review of the studies reveals a clear trend. The three studies that used lower dose levels and slower upward adjustment schedules (Fisman & Steele, 1996; Lombroso et al., 1995; McDougle et al., 1997) had a relatively low frequency of side effects, including EPS. The studies that used more rapid dose increases (perhaps derived from the schedules used in studies of adults with schizophrenia) had more adverse effects including EPS. In addition to these apparently dose-related side effects, in rare cases risperidone has been reported to cause elevation of liver enzymes with fatty infiltration of the liver (Kumra, Herion, Jacobsen, Briguglia, & Grothe,1997).

Olanzapine

Olanzapine is the most recent serotonin-dopamine antagonist to be marketed for the treatment of psychosis. It has been studied in adults with schizophrenia, but there are no published results describing the use of olanzapine in the pediatric population. Olanzapine is chemically related to clozapine and, like clozapine, retains greater potency for 5-HT^sub 2^ receptor blockade compared to D^sub 2^. Like clozapine, olanzapine blocks D^sub 4^ receptors, as well as histamine and adrenergic receptors. Unlike clozapine, olanzapine has not been associated with agranulocytosis.

In a recent multicenter study of 335 adults with schizophrenia, olanzapine was superior to placebo for both positive and negative symptoms (Bassly et al., 1996). In this study, subjects were randomly assigned to either placebo, haloperidol, or 3 -dose levels of olanzapine. At the medium dose (7.5-12.5 mg/day) and highest dose (12.5-17.5 mg/day), olanzapine was superior to placebo for both positive and negative symptoms. The highest dose level also was superior to haloperidol. The improvement on negative symptoms was evident at even the lowest dose level (2.5-7.5 mg/day), which was more effective than placebo. Haloperidol at doses ranging from 10-20 mg per day was more effective than placebo for positive symptoms, but showed little effect on negative symptoms. Quetiapine

The pharmacological profile of quetiapine appears to be somewhat different from that of the other atypical neuroleptics. Like the other members of this group, it has greater affinity for 5-HT^sub 2^ receptors than for D^sub 2^ receptors. However, it is relatively weak at both sites (Bymaster et al., 1996).

In a recent multicenter, double-blind study of 280 adults with schizophrenia, two doses of quetiapine were compared to placebo (Small, Hirsch, Arvanitis, Miller, & Link, 1997). As measured by the Brief Psychiatric Rating Scale, high-dose quetiapine (mean dose 488 mg/day) was superior to placebo and to low-dose quetiapine (mean dose 248 mg/day). Positive effects were evident after 14 days of treatment in the high-dose group, and there was no difference in the frequency of EPS across the three treatment groups. Side effects that were associated with quetiapine included tachycardia, postural hypotension, dizziness, and somnolence. Only 17 subjects withdrew because of adverse effects (14 from the active treatment groups), but approximately 50% in each group (high dose, low dose and placebo) withdrew because of treatment failure.

Conclusion

This new group of neuroleptics represents an important advance in psychopharmacology. The distinguishing feature of these compounds compared to traditional neuroleptics is their capacity to block both 5HT2 and D2 receptors. Indeed, the relative potency of the 5HT2 to D2 antagonism probably accounts for the differences within this group of new neuroleptics influencing both the side effect profile and the therapeutic applications as well. For example, clozapine, which has the highest 5HT2 to D2 ratio and is a weak D^sub 2^ antagonist, has not been associated with tardive dyskinesia. Whether tardive dyskinesia will be associated with the more potent D^sub 2^ blockers, such as risperidone, is uncertain. Nonetheless, in comparison to the traditional neuroleptics, the risk of long-term side effects such as tardive dyskinesia is likely to be lower with the new atypical neuroleptics.

The beneficial effects of these medications provide fertile ground for further research. Integrating the positive effects of these drugs and the limitations of the traditional neuroleptics with the evidence from animal and neuroimaging studies suggests that positive symptoms of schizophrenia are the result of dysregulation in subcortical circuits. Negative symptoms are the manifestation of prefrontal dysfunction.

Acknowledgments. This work was supported by the following USPHS grants: HD 03008, MH30929, and Program Project 49351 from the National Institute of Mental Health and Research Resources Grant RR00125 from the National Institutes of Health. Parts of this paper were presented at the annual meeting of the Association of Child & Adolescent Psychiatric Nurses in September 1996 in San Diego, CA. The conference received support from Janssen Pharmaceuticals, Solvay Pharmaceuticals, Gate Pharmaceuticals, Ridgewood Pharmaceuticals, and Abbott Pharmaceuticals. The authors acknowledge advice and collaboration from Drs. James Leckman, Robert A. King, Paul Lombroso, and Donald Cohen.

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Lawrence Scahill, PhD, RN, is Associate Research Scientist & Associate Clinical Professor of Nursing, and Kimberly A. Lynch, MSN, RN, is Clinical Nurse Specialist Yale Child Study Center, New Haven, CT.

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