Chapter 32. Risperidone and Paliperidone

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Donald C. Goff: Chapter 32. Risperidone and Paliperidone, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited

by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.418938.

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Chapter 32. Risperidone and Paliperidone

HISTORY AND DISCOVERY

A decade before clozapine was approved for marketing in the United States, Janssen Pharmaceuticals established a program

to examine the potential role of serotonergic agents in schizophrenia. Early interest in serotonergic agents stemmed from a

preclinical literature demonstrating that both behavioral effects of dopamine agonists and haloperidol-induced catalepsy

could be modulated by serotonin2 (5-HT2) antagonists; in addition, the early butyrophenone derivative pipamperone, which

was observed to reduce agitation and improve social activity in patients with severe depression, was found to possess

primarily 5-HT2 antagonist activity (Ansoms et al. 1977; Leysen et al. 1978).

In 1981, Janssen Pharmaceuticals developed setoperone, a 5-HT 2 antagonist with weak dopamine2 (D2) antagonism that

displayed antipsychotic effects and efficacy for negative symptoms in a preliminary open trial (Ceulemans et al. 1985).

Janssen Pharmaceuticals additionally synthesized a selective 5-HT 2A and 5-HT2C antagonist, ritanserin, which was shown to

decrease extrapyramidal side effects (EPS) when combined with haloperidol in rat studies. Ritanserin also was active in

animal models of anxiety (Colpaert and Meert 1985; Meert and Colpaert 1986) and partially ameliorated behavioral effects of

lysergic acid diethylamide (LSD) (Colpaert and Meert 1985). In placebo-controlled trials in patients with chronic

schizophrenia, addition of ritanserin to conventional antipsychotics improved negative symptoms and EPS (Bersani et al.

1990; Duinkerke et al. 1993; Gelders 1989; Reyntjens et al. 1986). Concluding that 5-HT 2 antagonism might improve efficacy

of D2 blockers, particularly for negative symptoms, and reduce EPS, but that it was not sufficiently effective as monotherapy,

Paul Janssen and colleagues undertook development of risperidone, which combined potent 5-HT 2A and D2 blockade.

After extensive preclinical characterization (Janssen et al. 1988), risperidone was first studied in clinical trials in 1986 and

received U.S. Food and Drug Administration (FDA) approval for marketing in the United States in 1994. By the time

risperidone became available to clinicians, the prominence of theories attributing 5-HT 2 enhancement of D2 antagonism as a

primary mechanism for clozapine’s atypical properties (Meltzer et al. 1989), and the evidence from registration trials of

reduced EPS and greater efficacy compared with high-dose haloperidol, resulted in considerable enthusiasm for the first of

the “serotonin–dopamine antagonists.” Risperidone was rapidly incorporated into clinical practice in the United States,

where within 2 years it became the most frequently prescribed antipsychotic agent. In 2003, risperidone microspheres

(Consta) received FDA approval as the first long-acting injectable second-generation antipsychotic. In December 2006,

Janssen Pharmaceuticals introduced paliperidone (9-hydroxyrisperidone), the active metabolite of risperidone, formulated

as an extended-release tablet marketed under the brand name Invega. A depot preparation, paliperidone palmitate, is

currently in late-stage development.

PHARMACOLOGICAL PROFILE

Risperidone, or

3-[2-(4-[6-fluoro-1,2-benzisoxazol-3-yl]-1-piperidinyl)ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,

is a benzisoxazole derivative (Figure 32–1) characterized by very high affinity for 5-HT 2A and moderately high affinity for D2,

H1, and 1- and 2-adrenergic receptors. In vitro, the affinity of risperidone for 5-HT 2A receptors is roughly 10- to 20-fold

greater than for D2 receptors (Leysen et al. 1994; Schotte et al. 1996); in vivo binding to rat striatal D 2 receptors occurs at a

dose 10 times higher than does binding to 5-HT 2A receptors (Leysen et al. 1994). The affinity for 5-HT 2A receptors is more

than 100-fold greater than for other serotonin receptor subtypes. The active metabolite 9-hydroxyrisperidone has a similar

receptor affinity profile. Both risperidone and 9-hydroxyrisperidone display high affinities for 5-HT 2A receptors in rat brain

tissue and for cloned human receptors expressed in COS-7 cells (Leysen et al. 1994). Risperidone binds to 5-HT 2A receptors

with approximately 20-fold greater affinity than clozapine and 170-fold greater affinity than haloperidol (Leysen et al.

1994).

FIGURE 32–1. Chemical structure of risperidone.

The affinity of risperidone for D2 receptors is approximately 50-fold greater than that of clozapine and approximately

20%–50% that of haloperidol (Leysen et al. 1994) (Table 32–1). Binding affinity for D 2 receptors was similar in rat

mesolimbic and striatal tissue and in the long and short forms of cloned human D 2 receptors expressed in embryonic kidney

cells (Leysen et al. 1993a). The affinities of risperidone and 9-hydroxyrisperidone for dopamine 4 (D4) and D1 receptors are Print: Chapter 32. Risperidone and Paliperidone http://www.psychiatryonline.com/popup.aspx?aID=418942&print=yes…

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similar to those of clozapine and haloperidol (Leysen et al. 1994). Risperidone has essentially no affinity for muscarinic

acetylcholine receptors and modest histaminergic H1 activity, whereas 9-hydroxyrisperidone minimally binds to H 1

receptors. Unlike haloperidol, risperidone does not bind to sigma sites (Leysen et al. 1994). However, compared with other

agents, risperidone has a relatively high affinity for 2-adrenergic receptors, which is substantially greater than that of

clozapine or any conventional agent and which approaches the affinity of phentolamine (Richelson 1996). The affinity of

risperidone for 1-adrenergic receptors is roughly comparable to that of chlorpromazine and approximately 5 to 10 times

greater than that of clozapine (Leysen et al. 1993b; Richelson 1996). The median effective dose (ED 50) of risperidone

required to inhibit D2-mediated apomorphine-induced stereotypies in rats is 0.5 mg/kg; at this dose, approximately 40% of

D2 receptors are occupied, as are 80% of 5-HT2A receptors, 50% of H1 receptors, 38% of 1-adrenergic receptors, and 10%

of 2-adrenergic receptors (Leysen et al. 1994).

TABLE 32–1. Receptor-binding affinities (Ki values, in nM) of risperidone (versus haloperidol and clozapine) in rat

Risperidone Haloperidol Clozapine

Dopaminergic

D2

3.1 1.2 152

D1

536 430 570

Serotonergic

5-HT2A

0.16 27 3.3

5-HT1A

420 1,500 145

Adrenergic

1

2.4 19 24

2

7.5 >10,000 159

H1 histaminergic 2.1 4,400 0.78

Muscarinic >10,000 4,400 33

Source. Adapted from Leysen et al. 1993b.

Several groups have studied the occupancy of D2 and 5-HT2 receptors in patients with schizophrenia, employing positron

emission tomography (PET) or single-photon emission computed tomography (SPECT) ligand-binding techniques. Kapur et

1. (1999) used PET to measure D2 occupancy with 11C-labeled raclopride and 5-HT2 occupancy with 18F-labeled setoperone

in patients with chronic schizophrenia maintained on a stable clinician-determined dose of risperidone. The PET was

performed 12–14 hours after the last dose of risperidone. Occupancy of D 2 receptors ranged from 63% to 89%; 50%

occupancy was calculated to occur with a daily risperidone dose of 0.8 mg. Patients treated with risperidone (6 mg/day)

exhibited a mean D2 occupancy of 79%, which was consistent with the mean occupancy of 82% that was previously reported

by Nyberg et al. (1999) and would be expected to exceed the putative threshold for EPS in some patients. A similar degree of

D2 occupancy was calculated to occur with olanzapine at approximately 30 mg daily (Kapur et al. 1999). A maximal 5-HT 2

occupancy of greater than 95% was achieved with risperidone at daily doses as low as 2–4 mg. In a small sample of patients

treated biweekly for at least 10 weeks with risperidone microspheres (Consta), Remington et al. (2006) found that the

25-mg dose produced a mean D2 occupancy of 54% (preinjection) and 71% (postinjection), whereas the 50-mg dose

produced occupancy levels of 65% (preinjection) and 74% (postinjection).

Preclinical characterization of risperidone in rats revealed more potent antiserotonergic activity, compared with ritanserin, in

all tests (Janssen et al. 1988). For example, in reversal of tryptophan-induced effects in rats, risperidone was 6.4 times more

potent than ritanserin for reversal of peripheral 5-HT 2-mediated effects and 2.4 times more potent for reversal of centrally

mediated 5-HT2 effects (Janssen et al. 1988). Risperidone was also found to completely block discrimination of LSD, in

contrast to the partial attenuation observed with ritanserin (Meert et al. 1989). Although risperidone demonstrated activity

in all dopamine-mediated tests, the dose–response pattern differed from that of haloperidol (Janssen et al. 1988). The two

drugs were roughly equipotent for inhibition of certain dopamine effects, such as amphetamine-induced oxygen

hyperconsumption, whereas the dose of risperidone necessary to cause pronounced catalepsy in rats was 18-fold higher

than that of haloperidol (Janssen et al. 1988). Risperidone depressed vertical and horizontal activity in rats at a dose 2–3

times greater than that of haloperidol but required doses more than 30 times greater than those of haloperidol to depress

small motor movements (Megens et al. 1988).

PHARMACOKINETICS AND DISPOSITION

Risperidone is rapidly absorbed after oral administration, with peak plasma levels achieved within 1 hour (Heykants et al.

1994). In early Phase I studies, risperidone demonstrated linear pharmacokinetics at dosages between 0.5 and 25 mg/day

(Mesotten et al. 1989; Roose et al. 1988). After a single dose of the extended-release formulation of paliperidone (Invega),

serum concentrations gradually increase until a maximum concentration is achieved approximately 24 hours after ingestion.

Absorption of paliperidone is increased by approximately 50% when taken with a meal compared with the fasted state.

Extended-release paliperidone also demonstrates dose-proportional pharmacokinetics within the recommended dosing range

(3–12 mg/day). Risperidone microspheres do not begin to release appreciable amounts of drug until 3 weeks after injection

and continue to release drug for approximately 4 weeks, with maximal drug release occurring after about 5 weeks.

Risperidone is 90% plasma protein bound, whereas 9-hydroxyrisperidone (paliperidone) is 74% plasma protein bound

(Borison 1994). The absolute bioavailability of risperidone is about 100%; that of extended-release paliperidone is aboutPrint: Chapter 32. Risperidone and Paliperidone http://www.psychiatryonline.com/popup.aspx?aID=418942&print=yes…

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28%.

Risperidone is metabolized by hydroxylation of the tetrahydropyridopyrimidinone ring at the seven and nine positions and by

oxidative N-dealkylation (Mannens et al. 1993). The most important metabolite, 9-hydroxyrisperidone, accounts for up to

31% of the dose excreted in the urine and has a receptor affinity profile similar to that of the parent compound. Because

hydroxylation of risperidone is catalyzed by cytochrome P450 (CYP) 2D6, the half-life of the parent compound varies

according to the relative activity of this enzyme. In “extensive metabolizers,” which include about 90% of Caucasians and as

many as 99% of Asians, the half-life of risperidone is approximately 3 hours. In healthy subjects, approximately 60% of

9-hydroxyrisperidone is excreted unchanged in the urine, and the remainder is metabolized by at least four different

pathways (dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission), none of which accounts for more than

10% of the total. The terminal half-life of 9-hydroxyrisperidone (and of extended-release paliperidone) is 23 hours. “Poor

metabolizers” metabolize risperidone primarily via oxidative pathways; the half-life may exceed 20 hours. In extensive

metabolizers, radioactivity from 14C-labeled risperidone is not detectable in plasma 24 hours after a single dose, whereas

9-hydroxyrisperidone accounts for 70%–80% of radioactivity. In poor metabolizers, risperidone is primarily responsible for

radioactivity after 24 hours. In the U.S. multicenter registration trial, the correlations between risperidone dose and serum

risperidone and 9-hydroxyrisperidone concentrations were 0.59 and 0.88, respectively (Anderson et al. 1993).

MECHANISM OF ACTION

As previously discussed, risperidone was developed specifically to exploit the apparent pharmacological advantages of

combining 5-HT2 antagonism with D2 blockade. Selective 5-HT2A antagonists administered alone have demonstrated activity

in several animal models suggestive of antipsychotic effect, including blockade of both amphetamine- and phencyclidine

(PCP)–induced locomotor activity (Schmidt et al. 1995). Dizocilpine-induced disruption of prepulse inhibition is also blocked

by 5-HT2A antagonists, suggesting that sensory gating deficits characteristic of schizophrenia and perhaps resulting from

glutamatergic dysregulation might also benefit from the 5-HT2 antagonism of risperidone (Varty et al. 1999). The disruption

of prepulse inhibition by dizocilpine (MK-801, a noncompetitive N-methyl-D-aspartate [NMDA] antagonist) is attenuated by

atypical antipsychotics, but not by conventional D2 blockers (Geyer et al. 1990). From a study in which the selective 5-HT 2A

antagonist M100907 was added to low-dose raclopride (a selective D 2 blocker), Wadenberg et al. (1998) concluded that

5-HT2A antagonism facilitates D2 antagonist blockade of conditioned avoidance, another behavioral model associated with

antipsychotic efficacy, but does not block conditioned avoidance when administered alone.

One mechanism by which risperidone, paliperidone, and similar atypical agents might produce enhanced efficacy for

negative symptoms and cognitive deficits and reduced risk for EPS is via 5-HT 2A receptor modulation of dopamine neuronal

firing and cortical dopamine release. Prefrontal dopaminergic hypoactivity has been postulated to underlie negative

symptoms and cognitive deficits in schizophrenia (Goff and Evins 1998); both clozapine and ritanserin have been shown to

increase dopamine release in prefrontal cortex, whereas haloperidol does not (Busatto and Kerwin 1997). Following 21 days

of administration, risperidone, but not haloperidol, continued to increase dopamine turnover in the dorsal striatum and

prefrontal cortex (Stathis et al. 1996). Ritanserin has been shown to enhance midbrain dopamine cell firing by blocking a

tonic inhibitory serotonin input (Ugedo et al. 1989). Ritanserin also normalized ventral tegmental dopamine neuron firing

patterns in rats after hypofrontality was induced by experimental cooling of the frontal cortex (Svensson et al. 1989).

Svensson et al. (1995) have performed a series of elegant studies examining the impact of atypical antipsychotics on ventral

tegmental dopamine firing patterns disrupted by glutamatergic NMDA receptor antagonists. In healthy human subjects,

administration of the NMDA antagonist ketamine is widely regarded as a promising model for several clinical aspects of

schizophrenia, including psychosis, negative symptoms, and cognitive deficits (Goff and Coyle 2001; Krystal et al. 1994). In

rats, administration of the NMDA channel blockers dizocilpine or PCP increased burst firing of ventral tegmental dopamine

neurons predominately projecting to limbic structures but reduced firing of mesocortical tract dopamine neurons and

disrupted firing patterns. Administration of ritanserin and clozapine preferentially enhanced firing of dopamine neurons with

cortical projections, and when added to a D2 blocker, ritanserin increased dopamine release in prefrontal cortex. In addition

to modulating ventral tegmental dopamine neuron firing, risperidone also blocks 5-HT 2 receptors on inhibitory

-aminobutyric acid (GABA)-ergic interneurons, which could also influence activity of cortical pyramidal neurons that are

regulated by these local inhibitory circuits (Gellman and Aghajanian 1994).

In placebo-controlled clinical trials, 5-HT2 antagonists have reduced antipsychotic-induced parkinsonism and akathisia

(Duinkerke et al. 1993; Poyurovsky et al. 1999). This effect may reflect 5-HT 2A antagonist effects upon nigrostriatal

dopamine release. When combined with haloperidol, selective 5-HT 2 antagonists increase dopamine metabolism in the

striatum and prevent an increase in D2 receptor density, thereby possibly reducing the effects of D2 receptor blockade and

dopamine supersensitivity (Saller et al. 1990). These agents do not affect dopamine metabolism in the absence of D 2

blockade.

The relative importance of 5-HT2 antagonist activity in producing atypical characteristics is the subject of debate. As argued

by Kapur and Seeman (2001) and Seeman (2002), most atypical antipsychotic agents have dissociation constants for the D 2

receptor that are larger than the dissociation constant of dopamine. This “loose binding” to the D 2 receptor may allow

displacement by endogenous dopamine and may contribute to a reduced liability for EPS and hyperprolactinemia. Unique

among atypical agents, risperidone is “tightly bound” to the D2 receptor, with a dissociation constant smaller than that of

dopamine (Seeman 2002). A model for atypical antipsychotic mechanisms that emphasizes D 2 dissociation constants would

predict that the apparent atypicality of risperidone, compared with that of haloperidol, reflects the reduced D 2 occupancy

achieved by more favorable dosing rather than the intrinsic pharmacological characteristics of risperidone. According to

some binding data, a comparable clinical dosage of haloperidol would be approximately 4 mg/day, rather than 20 mg/day as

used in the North American multicenter registration trial (Kapur et al. 1999). Consistent with this view, benefits of

risperidone for negative symptoms and EPS were less apparent when compared with lower doses of haloperidol or withPrint: Chapter 32. Risperidone and Paliperidone http://www.psychiatryonline.com/popup.aspx?aID=418942&print=yes…

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lower-potency conventional agents (see “Indications and Efficacy” section later in this chapter) than when compared with

high-dose haloperidol (20 mg/day).

An additional mechanism possibly contributing to the enhanced efficacy of risperidone and paliperidone is their considerable

-adrenergic antagonism. In a placebo-controlled augmentation trial, Litman et al. (1996) demonstrated significant

improvement in psychosis and negative symptoms with the 2-adrenergic antagonist idazoxan when it was added to

conventional antipsychotics. Idazoxan has been shown to increase dopamine levels in the rat medial prefrontal cortex

(Hertel et al. 1999). In aged rats (Haapalinna et al. 2000) and in patients with frontal dementias (Coull et al. 1996),

2-adrenergic blockers have also been reported to improve cognitive functioning. Svensson et al. (1995) found that prazosin,

an 1 antagonist, inhibited both behavioral activation and the increase in mesolimbic dopamine release produced by PCP or

MK-801.

In summary, risperidone and paliperidone possess at least two mechanisms that may confer atypical characteristics. 5-HT 2A

antagonism partially protects against D2 antagonist–induced neurological side effects and may improve negative symptoms

and cognitive functioning via modulation of mesocortical dopamine activity. In addition, blockade of adrenoceptors may

further increase prefrontal cortical activity and could enhance antipsychotic efficacy by modulation of mesolimbic dopamine

activity. Unlike other atypical agents, risperidone and paliperidone do not differ from conventional agents in their

dissociation constant for the D2 receptor; this feature perhaps accounts for the risk of EPS at high doses, as well as their

greater propensity to cause hyperprolactinemia.

INDICATIONS AND EFFICACY

Risperidone is approved by the FDA for the treatment of schizophrenia, bipolar mania, and irritability associated with autism.

In August 2007, the indication for schizophrenia was extended to include adolescents ages 13–17 years, and the bipolar

mania indication was extended to include children 10–17 years of age. Risperidone microspheres (Consta long-acting

injection) and extended-release paliperidone (Invega) are approved for the treatment of schizophrenia.

Schizophrenia

Clinical Trial Results for Risperidone

In the two North American registration trials (Chouinard et al. 1993; Marder and Meibach 1994), a total of 513 patients with

chronic schizophrenia were randomly assigned to an 8-week double-blind, fixed-dose, placebo-controlled comparison of

risperidone (2, 6, 10, or 16 mg/day) or haloperidol (20 mg/day). Risperidone dosages of 6, 10, and 16 mg/day produced

significantly greater reductions, as compared with haloperidol, in each of the five domains of the Positive and Negative

Syndrome Scale (PANSS), derived by principal-components analysis (Marder et al. 1997), and significantly higher response

rates, defined as a 20% reduction in the PANSS total score. Effect sizes representing the difference in change scores

between risperidone (6 mg/day) and haloperidol, although statistically significant, were uniformly small by Cohen’s

classification system (Cohen 1988): negative symptoms 0.31; positive symptoms 0.26; disorganized thoughts 0.22;

uncontrolled hostility/excitement 0.29; and anxiety/depression 0.30 (Table 32–2). Severity of EPS was greater with

haloperidol than with risperidone; further statistical analysis suggested that differences in EPS rates did not significantly

influence the differences in PANSS subscale ratings (Marder et al. 1997). In fact, risperidone (10 and 16 mg/day) produced

improvements in negative symptoms equivalent to those seen with risperidone (6 mg/day), despite increased EPS at the

higher dosages of risperidone.

TABLE 32–2. Effect sizes on Positive and Negative Syndrome Scale (PANSS) symptom dimensions: North American trials ( N

= 513)

Adjusted mean change scores Risperidone 6 mg/day

Placebo Risperidone 6 mg/day Haloperidol Effect size vs. placebo Effect size vs. haloperidol

PANSS total –3.8 –18.6 –5.1 0.53 0.31

Negative

0.2 –3.4 –0.1 0.27 0.26

Positive

0.9 –5.7 –2.3 0.48 0.22

Disorganized thought

0.1 –4.6 –0.2 0.43 0.24

Hostility/excitement

0.2 –2.5 –0.1 0.47 0.29

Anxiety/depression

–0.1 –2.5 –0.6 0.36 0.30

Source. Adapted from Marder et al. 1997.

When risperidone (1, 4, 8, 12, and 16 mg/day) was compared with haloperidol (10 mg/day) in a large 8-week European trial

involving 1,362 subjects with schizophrenia (Peuskens 1995), PANSS subscale change scores indicated preferential

response to daily risperidone doses of 4 and 8 mg. However, neither the risperidone group taken as a whole nor individual

risperidone doses achieved significantly better outcomes than haloperidol (10 mg/day) on any measure except for EPS,

suggesting that the degree of the clinical superiority of risperidone, compared with haloperidol, may be dependent on the

dosing of the comparator.

In the National Institute of Mental Health–funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE; Stroup

et al. 2003), 1,432 patients with chronic schizophrenia were randomly assigned to double-blind, flexibly dosed treatment for

18 months with risperidone, olanzapine, quetiapine, ziprasidone, or the conventional antipsychotic comparator

perphenazine. Clinicians could adjust the dosage of each drug by prescribing 1–4 capsules daily; risperidone capsulesPrint: Chapter 32. Risperidone and Paliperidone http://www.psychiatryonline.com/popup.aspx?aID=418942&print=yes…

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contained 1.5 mg, and the mean daily dose administered in the study was 3.9 mg. Based on the primary outcome measure,

time to all-cause discontinuation, risperidone was less effective than olanzapine (mean dosage = 20 mg/day) and

comparable in effectiveness to perphenazine (mean dosage = 21 mg/day) and the other atypical agents (Lieberman et al.

2005). Although differences in rates of dropout due to intolerance did not reach statistical significance, risperidone

consistently was the best-tolerated drug, particularly in subjects who had failed their first-assigned drug due to intolerance.

Whereas the superior efficacy of risperidone for acute symptom reduction, compared with haloperidol, is quite broad (but of

relatively small magnitude) and may be determined in part by the haloperidol dose, efficacy for prevention of relapse

appears to be of a substantially greater relative magnitude. For example, Csernansky et al. (2002) randomly assigned 365

patients with stable schizophrenia or schizoaffective disorder to clinician-determined flexible dosing with risperidone or

haloperidol for a minimum of 1 year. Kaplan-Meier estimates of the risk of relapse at the end of the study were 34% with

risperidone, compared with 60% with haloperidol, a highly significant difference ( P = 0.001).

Several studies have indicated that risperidone may significantly enhance cognitive functioning, particularly verbal working

memory, compared with haloperidol (Green et al. 1997). More recently, in a large double-blind, flexibly dosed 3-month trial

in first-episode schizophrenia patients, risperidone (mean dosage = 3.2 mg/day) produced a modest, although statistically

significant, improvement in the composite cognitive score compared with haloperidol (mean dosage = 2.9 mg/day) (Harvey

et al. 2005). Another large double-blind trial examined cognitive effects in chronic schizophrenia patients treated for 52

weeks with risperidone (mean dosage = 5.2 mg/day), olanzapine (12.3 mg/day), and haloperidol (8.2 mg/day) (Keefe et al.

2006). No difference between treatments was found in improvement on the composite cognitive score, although risperidone

and olanzapine were superior to haloperidol in a secondary analysis of completers (Keefe et al. 2006). No significant

differences in cognitive effects were found among risperidone, perphenazine, or the other atypical antipsychotics in the

CATIE (Keefe et al. 2007).

Risperidone has been found to be well tolerated and effective in subgroups of patients with schizophrenia, including

first-episode patients and elderly patients. In a 4 month double-blind trial comparing risperidone (mean dosage = 3.9

mg/day) and olanzapine (mean dosage = 11.8 mg/day) in 112 first-episode patients, both treatments were well tolerated,

with an overall completion rate of 72% (Robinson et al. 2006). Response rates did not differ significantly between

risperidone (54%) and olanzapine (44%), although patients who responded to risperidone were significantly more likely to

retain their response. Experience with patients with treatment-resistant schizophrenia has been less consistent. In the U.S.

multicenter registration study, Marder and Meibach (1994) found that patients who were presumed to have failed to respond

to conventional agents, on the basis of a history of hospitalization for at least 6 months prior to study entry, did not respond

to haloperidol (20 mg/day) but did display significant response to risperidone (6 and 16 mg/day), compared with placebo.

Wirshing et al. (1999) reported significant improvement with risperidone (6 mg/day), compared with haloperidol (15

mg/day), during a 4 week fixed-dose trial in 67 patients with schizophrenia and histories of treatment resistance. However,

the difference between treatments was lost during a subsequent 4 week flexible-dose phase in which the mean risperidone

dosage was increased to 7.5 mg/day and the mean haloperidol dosage was increased to 19.4 mg/day. Bondolfi et al. (1998)

reported comparable significant improvement with risperidone (mean dosage = 6.4 mg/day) and clozapine (mean dosage =

292 mg/day) in a randomized, double-blind trial involving 86 patients with schizophrenia described as resistant or intolerant

to conventional antipsychotics by history. In a large open trial, risperidone produced significantly higher response rates than

did haloperidol in 184 patients with histories of poor response (Bouchard et al. 2000). The relative superiority of risperidone

over haloperidol steadily increased over time, reaching a maximum at the conclusion of the 12-month study. In contrast,

Volavka et al. (2002) found no difference between high-dose risperidone (8–16 mg/day) and haloperidol (10–20 mg/day) in

patients established by history to be treatment resistant to conventional antipsychotics. In the CATIE, risperidone was more

effective than quetiapine but did not differ from olanzapine and ziprasidone in patients who discontinued their first-assigned

atypical antipsychotic medication due to lack of efficacy (Stroup et al. 2006). In contrast, patients who discontinued

perphenazine (for any reason) subsequently did better on quetiapine or olanzapine than they did on risperidone (Stroup et

1. 2007).

Clinical Trial Results for Paliperidone

Extended-release paliperidone (Invega) at dosages of 6, 9, and 12 mg/day was more effective than placebo in a 6-week trial

in acutely ill schizophrenia patients (Kane et al. 2007). In a flexibly dosed trial, extended-release paliperidone (9–15

mg/day) significantly reduced relapse compared with placebo (Kramer et al. 2007). The long-acting risperidone microsphere

(Consta) formulation at fixed doses of 25 mg, 50 mg, and 75 mg administered biweekly was also superior in efficacy to

placebo in a 12-week trial (Kane et al. 2003). In a 52-week study, treatment with risperidone microspheres was associated

with low relapse rates; the incidence of relapse was 21.6% with the 25-mg dose and 14.9% with the 50-mg dose

administered every 2 weeks (Simpson et al. 2006). In an open-label pilot trial of risperidone microspheres administered at a

dose of 50 mg every 4 weeks, the 1-year relapse rate was estimated to be 22.4% (Gharabawi et al. 2007).

Affective Disorders

Six controlled trials of 3–4 weeks’ duration that included a total of 1,343 patients have examined the efficacy of risperidone

as monotherapy or in combination with a mood stabilizer for the acute treatment of bipolar mania (Rendell et al. 2006). As

monotherapy and in combination, risperidone was more effective than placebo and comparable to haloperidol (Rendell et al.

2006). Risperidone’s comparative efficacy in long-term prevention of relapse in bipolar disorder has not been established

(Rendell and Geddes 2006).

Risperidone 1–2 mg/day was evaluated as an adjunct to antidepressant therapy in a 4-week placebo-controlled trial in 174

antidepressant-resistant patients with major depression recruited from 19 primary care and psychiatric centers (Mahmoud

et al. 2007). Risperidone significantly lowered ratings of depressive symptoms compared with placebo. Remission rates werePrint: Chapter 32. Risperidone and Paliperidone http://www.psychiatryonline.com/popup.aspx?aID=418942&print=yes…

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25% with risperidone versus 11% with placebo ( P = 0.004). Risperidone was well tolerated, with an 81% completion rate

(vs. 88% with placebo).

Autism

Risperidone was also studied in a large 8-week placebo-controlled trial in 101 children (ages 5–17 years) with autism

accompanied by severe tantrums, aggression, or self-injurious behavior (McCracken et al. 2002). Flexible dosing with

risperidone (range = 0.5–3.5 mg/day; mean dosage = 1.2 mg/day) resulted in a mean reduction of 57% in irritability,

compared with a decrease of 14% in the placebo group, and the response rate was 69% with risperidone versus 12% with

placebo. In a study of 32 children (ages 5–17 years) treated for 4 months with open-label risperidone (mean dosage = 2

mg/day), those who continued treatment with risperidone during the second study arm, an 8-week double-blind substitution

trial, had much lower relapse rates than patients switched to placebo (Research Units on Pediatric Psychopharmacology

Autism Network 2005). Risperidone at a mean dosage of 2 mg/day was also found to be effective compared with placebo in

a study of 31 adults with autism or pervasive developmental disorder (McDougle et al. 1998). In these studies, risperidone

improved irritability and behavioral problems associated with autism but was not effective for social or language deficits.

Risperidone at a dosage of 0.02–0.06 mg/kg was found to be well tolerated and effective for disruptive behaviors in children

with low intelligence (intelligence quotient [IQ] between 36 and 84) in a 6-week placebo-controlled trial (Aman et al. 2002).

Other Disorders

In a 4-week placebo-controlled trial in 417 patients with generalized anxiety disorder, anxiety symptoms improved to a

similar degree in both the placebo and the risperidone groups (Pandina et al. 2007). Risperidone was highly effective for

obsessive-compulsive disorder symptoms in a 6-week placebo-controlled trial in 36 adults prospectively confirmed to be

refractory to treatment with a selective serotonin reuptake inhibitor (McDougle et al. 2000). Symptoms of anxiety and

depression also responded to risperidone compared with placebo. Fifty percent of risperidone-treated patients responded

(mean dosage = 2.2 mg/day), compared with 0% in the placebo group.

SIDE EFFECTS AND TOXICOLOGY

Risperidone shares class warnings with other atypical antipsychotics in the United States, including the risks of tardive

dyskinesia, neuroleptic malignant syndrome, and hyperglycemia and diabetes, as well as the risk of increased mortality in

elderly patients with dementia-related psychosis. However, risperidone generally has been very well tolerated in clinical

trials. In the U.S. multicenter trial reported by Marder and Meibach (1994), only headache and dizziness were significantly

more frequent with risperidone (6 mg/day), compared with placebo, whereas the group receiving risperidone (16 mg/day)

treatment also reported more EPS and dyspepsia than did the group receiving placebo (Table 32–3). Fatigue, sedation,

accommodation disturbances, orthostatic dizziness, palpitations or tachycardia, weight gain, diminished sexual desire, and

erectile dysfunction displayed a statistically significant relationship to risperidone dose, although most were not significantly

elevated compared with placebo. In a flexible-dose relapse prevention study reported by Csernansky et al. (2002), no side

effects were more frequent with risperidone, compared with haloperidol, although risperidone produced significantly greater

weight gain. In a flexibly dosed, placebo-controlled trial of risperidone for children with disruptive behavior, risperidone

(mean dosage = 1.2 mg/day) produced more somnolence, headache, vomiting, dyspepsia, weight gain, and prolactin

elevation than did placebo; most side effects were rated mild to moderate and did not adversely affect compliance (Aman et

1. 2002).

TABLE 32–3. Side effects reported by patients with schizophrenia receiving placebo, risperidone, or haloperidol in the U.S.

multicenter trial

Percentage of patients

Placebo (n = 66) Risperidone 6 mg (n = 64) Risperidone 16 mg (n = 64) Haloperidol (n = 66)

Insomnia 9.1 12.5 9.4 12.1

Agitation 7.6 10.9 12.5 16.7

Anxiety 1.5 7.8 4.7 1.5

Nervousness 1.5 6.3 1.6 0

Somnolence 0 3.1

9.4a

4.5

Extrapyramidal side effects 10.6 10.9

25.0a

25.8a

Headache 4.5

15.6a

9.4 7.6

Dizziness 0

9.4a

10.9b

0

Dyspepsia 4.5 9.4 6.3 4.5

Vomiting 1.5 6.3 6.3 3.0

Nausea 0 6.3 3.1 1.5

Constipation 0 1.6 6.3 1.5

Rhinitis 6.1 15.6 6.3 4.5

Coughing 1.5 9.4 3.1 3.0

Sinusitis 1.5 6.3 1.6 0

Fever 0 6.3 3.1 1.5Print: Chapter 32. Risperidone and Paliperidone http://www.psychiatryonline.com/popup.aspx?aID=418942&print=yes…

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Percentage of patients

Placebo (n = 66) Risperidone 6 mg (n = 64) Risperidone 16 mg (n = 64) Haloperidol (n = 66)

Tachycardia 0 4.7 6.3 1.5

aP <0.05 versus placebo.

bP <0.01 versus placebo.

Source. Adapted from Marder and Meibach 1994.

Weight gain with risperidone is intermediate—that is, the degree of weight gain is between that associated with agents like

molindone and ziprasidone, which appear to be relatively weight neutral, and that associated with agents like clozapine,

olanzapine, and low-potency phenothiazines. In a meta-analysis of controlled trials, Allison et al. (1999), using a random

effects model, estimated the mean weight gain at 10 weeks with risperidone to be 2.0 kg, compared with 0.5 kg with

haloperidol, 3.5 kg with olanzapine, and 4.0 kg with clozapine. Although determining the risk for hyperglycemia is complex,

and results of studies have not been completely consistent, it appears that risperidone does not produce insulin resistance

and dyslipidemia to the degree associated with olanzapine and clozapine (American Diabetes Association et al. 2004;

Henderson et al. 2006; Lieberman et al. 2005). In the CATIE, risperidone was associated with the lowest rate of

discontinuation due to side effects (Lieberman et al. 2005). Risperidone treatment resulted in a mean 0.4-lb weight gain per

month, compared with 2.0 lbs with olanzapine, 0.5 lb with quetiapine, and a mean monthly weight loss of 0.2 lb with

perphenazine and 0.3 lb with ziprasidone.

Mesotten et al. (1989) reported the results of a safety trial involving 17 inpatients with psychosis in which, following a

washout of previous medication, risperidone was started at 10 mg/day, and the dosage was then increased weekly by 5

mg/day to a maximum of 25 mg/day. Despite extremely high doses, sedation was the only prominent side effect. Although

risperidone does not bind significantly to muscarinic cholinergic receptors, transient dry mouth, blurred vision, and urinary

retention were observed in individual subjects. Palpitations occurred in 2 subjects. Heart rate significantly increased during

the trial, and blood pressure slightly decreased; however; no cases of significant hypotension were reported. An endocrine

battery, including plasma triiodothyronine, thyroid-stimulating hormone, growth hormone, prolactin, follicle-stimulating

hormone, luteinizing hormone, and cortisol levels, was performed, and only prolactin was found to be affected.

Extrapyramidal Side Effects

Significant reductions in EPS with risperidone, compared with high-dose haloperidol, were a consistent finding in the North

American trials (Chouinard et al. 1993; Marder and Meibach 1994). Measurement of EPS in the placebo group was

complicated because 25% of the subjects were taking depot antipsychotics prior to enrollment. Risperidone produced

significantly fewer parkinsonian side effects than did haloperidol (20 mg/day), based on several measures, including

self-report, change scores on the Extrapyramidal Symptom Rating Scale (ESRS), and use of anticholinergic medication.

Patients receiving risperidone (2 and 6 mg/day) did not differ from the group receiving placebo in mean ratings of

parkinsonism and in the use of anticholinergic medication. Parkinsonism change scores were significantly correlated with

the risperidone dosage (r = 0.94); however, risperidone (16 mg/day) was associated with fewer parkinsonian side effects

than was haloperidol. Dystonia occurred in six of the patients treated with risperidone (1.7%) versus two of the patients

treated with haloperidol (2.4%). Dystonia rates did not differ between treatment groups, and the rates did not exhibit a

relationship to risperidone dosage.

In the large European multicenter trial, maximum ratings of parkinsonism, hyperkinesias, and dystonia were greater with

haloperidol (10 mg/day) than with all dosages of risperidone (maximum of 12 mg/day), and anticholinergic dosing was

accordingly higher in the group treated with haloperidol (Peuskens 1995). Similarly, in a flexible-dose comparison of

risperidone (mean dosage = 4.9 mg/day) and haloperidol (mean dosage = 11.7 mg/day) for prevention of relapse, EPS rates

and use of anticholinergic medication significantly favored the group taking risperidone (Csernansky et al. 2002). However,

in a smaller double-blind, flexible-dose trial comparing risperidone (5–15 mg/day) and the moderate-potency conventional

agent perphenazine (16–48 mg/day) in 107 patients, no difference in EPS rates was observed (Hoyberg et al. 1993),

indicating that the potency of the comparator agent may in part determine the relative benefit of risperidone for EPS. Of

interest, in a study of low-dose risperidone (mean dosage = 1.16 mg/day) in children with behavioral disorders, ratings of

EPS did not differ between risperidone and placebo (Aman et al. 2002). No differences in EPS ratings were found between

any treatment groups in the CATIE (Lieberman et al. 2005), although discontinuation rates due to EPS significantly differed,

with perphenazine producing the highest discontinuation rate (8%) and olanzapine (2%), risperidone (3%), and quetiapine

(3%) producing the lowest.

The experience with tardive dyskinesia (TD) in patients treated with risperidone has been quite promising. Jeste et al.

(1999) randomly treated 122 elderly patients with low-dose haloperidol (median dose = 1 mg) versus risperidone (median

dose = 1 mg). The very high rates of treatment-emergent TD typically found in geriatric patients make this sample a

sensitive assay for TD risk. After 9 months, treatment-emergent TD rates were 30% with haloperidol versus less than 5%

with risperidone. Risperidone was also noted to decrease dyskinetic movements, compared with haloperidol, in a Canadian

multicenter trial reported by Chouinard et al. (1993), and it was associated with a treatment-emergent TD rate of 0.6%,

compared with a rate of 2.7% with haloperidol, in a relapse prevention trial reported by Csernansky et al. (2002).

Hyperprolactinemia

Unlike other atypical antipsychotic agents, risperidone substantially increases serum prolactin levels—in some studies, to a

greater degree than does haloperidol (Kearns et al. 2000; Markianos et al. 1999). The relationship between serum prolactin

concentrations and clinical side effects remains somewhat unclear, however. Kleinberg et al. (1999) analyzed combined

results from the North American and European multicenter registration trials, which included plasma prolactinPrint: Chapter 32. Risperidone and Paliperidone http://www.psychiatryonline.com/popup.aspx?aID=418942&print=yes…

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concentrations from 841 patients and clinical ratings of symptoms associated with hyperprolactinemia from 1,884 patients.

Mean prolactin levels significantly correlated with risperidone dosage; risperidone 6 mg/day produced elevations roughly

comparable to those seen with haloperidol 20 mg/day and significantly higher than those seen with haloperidol 10 mg/day.

The combined incidence of amenorrhea and galactorrhea in women, which varied between 8% and 12%, was similar for all

dosages of risperidone and haloperidol (10 mg/day). Because symptom frequencies were available only for 14 women

treated with placebo, comparisons with placebo were not informative. Sexual dysfunction or gynecomastia occurred in 15%

of men treated with risperidone (4–6 mg/day), compared with 14% of men treated with haloperidol (10 mg/day) and 8% of

men in the placebo group. Compared with placebo, ejaculatory dysfunction was significantly more frequent only in the group

treated with risperidone (12–16 mg/day). Mean plasma prolactin levels were not significantly related to clinical side effects

for either men or women. Decreased libido also did not differ between treatment groups and did not correlate with plasma

prolactin levels. In the CATIE, prolactin levels increased by a mean of 15.4 ng/mL with risperidone, compared with a

0.4-ng/mL mean elevation with perphenazine and decreases of 4.5–9.3 ng/mL with the other atypical agents (Lieberman et

1. 2005). Despite having significantly higher serum prolactin concentrations, patients treated with risperidone did not

report significantly higher rates of sexual dysfunction, gynecomastia, galactorrhea, or irregular menses.

Two reports of clinical trials with extended-release paliperidone have indicated low levels of prolactin-related side effects

(1% and 4%) (Kane et al. 2007; Kramer et al. 2007). However, in the one publication that reported prolactin levels,

substantial increases in mean plasma prolactin concentrations were observed (males: 17.4 ng/mL at baseline to 45.3 ng/mL

at week 6; females: 38.0 ng/mL to 124.5 ng/mL) (Kane et al. 2007). Two preliminary studies with risperidone found that

plasma prolactin concentrations correlated with 9-hydroxyrisperidone (paliperidone) concentrations and not with

risperidone concentrations (Melkersson 2006; Troost et al. 2007). The ratio of 9-hydroxyrisperidone levels to risperidone

levels also correlated with prolactin concentration (Troost et al. 2007); in agreement with this finding, rapid metabolizers of

CYP2D6 were found to have higher prolactin concentrations than poor metabolizers (Troost et al. 2007). Because of the

difficulty in establishing dose equivalence between risperidone and paliperidone in clinical trials, it is not clear whether the

two drugs differ in their potential to elevate prolactin. Additional studies are needed to compare prolactin elevations with

the two drugs.

Cardiovascular Effects

Because of relatively high affinities for adrenoreceptors, risperidone would be expected to produce orthostatic hypotension.

However, by following a 3- to 7-day dosage escalation schedule, initial postural hypotension and tachycardia have been

avoided in clinical trials, with only rare cases of hypotension and syncope reported (Chouinard et al. 1993; Marder and

Meibach 1994). Risperidone has very modest effects on cardiac conduction. No significant prolongation of the QTc interval

was detected at dosages of up to 25 mg/day in early safety trials, and no relationship between QTc interval and risperidone

dose was apparent (Mesotten et al. 1989). In the CATIE, risperidone was associated with the least QTc prolongation (mean

0.2 msec) and quetiapine with the greatest (mean 5.9 msec), although differences were not statistically significant

(Lieberman et al. 2005). A mean 10-msec prolongation of the QTc, measured after peak absorption of risperidone (16

mg/day), was found in a study comparing atypical and typical antipsychotic agents, according to data filed with the FDA by

Pfizer Inc. (Harrigan et al. 2004). Reported overdoses with risperidone have generally been benign, with moderate QT

prolongation and no serious cardiac complications (Brown et al. 1993; Lo Vecchio et al. 1996).

DRUG–DRUG INTERACTIONS

Because CYP2D6 status affects the half-life of risperidone and the relative ratio of risperidone to 9-hydroxyrisperidone in

plasma, the total serum concentration of the “active moiety,” or risperidone plus 9-hydroxyrisperidone, may be significantly

increased with addition of a CYP2D6 inhibitor (e.g., fluoxetine) in rapid metabolizers but not in poor metabolizers (Bondolfi

et al. 2002; Spina et al. 2002). Paliperidone plasma concentrations are not influenced by CYP2D6 status, nor are

paliperidone plasma concentrations likely to be affected by drug–drug interactions. It is possible that the addition of a

CYP2D6 inhibitor (e.g., fluoxetine) could decrease risperidone-induced prolactin elevation by increasing the ratio of

risperidone to 9-hydroxyrisperidone (Troost et al. 2007).

CONCLUSION

Risperidone was the first antipsychotic agent developed specifically to exploit the clinical advantages of combined D 2 and

5-HTA2 antagonism. -Adrenergic antagonism additionally may contribute to the antipsychotic and cognitive-enhancing

effects of risperidone. Risperidone is generally quite well tolerated, producing only moderate weight gain and mild sedation.

Initial dosage titration is necessary to prevent orthostatic blood pressure changes and dizziness, although this may be less

necessary with extended-release paliperidone. EPS are dose related, but their incidence at dosages less than or equal to 6

mg/day has not significantly differed from placebo. Risperidone substantially elevates prolactin levels, although the

relationship between plasma prolactin concentrations and clinical symptoms is complex; prolactin-related side effects have

not been detected in several studies of risperidone and paliperidone despite considerable prolactin elevation. The efficacy of

risperidone is well established; compared with high-dose haloperidol, risperidone (6 mg/day) is significantly more effective

for all five symptom clusters derived from the PANSS. Although it is broadly more effective, the magnitude of difference in

effect size is not large for individual symptom clusters. At a dosage of 3.9 mg/day, risperidone did not differ from

perphenazine in rates of discontinuation due to lack of effectiveness in the CATIE (Lieberman et al. 2005). Perhaps most

impressive has been evidence indicating that risperidone is substantially more effective than haloperidol in preventing

relapse. Evidence of enhanced cognitive functioning with risperidone, with particular benefits for verbal memory, is

encouraging, although also of a relatively modest magnitude. The availability of risperidone microspheres (Consta), the first

long-acting injectable atypical agent, represents an important advance with the potential both to improve compliance and to

minimize peak serum drug concentrations associated with oral dosing. While extended-release paliperidone also produces

more uniform serum concentrations and avoids the variability associated with CYP2D6 status, the possibility of greaterPrint: Chapter 32. Risperidone and Paliperidone http://www.psychiatryonline.com/popup.aspx?aID=418942&print=yes…

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prolactin elevation with this formulation requires further study.

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