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GOAL

The goals of this lesson are to become familiar with the currently available evidence for lower dosing of some atypical antipsychotic agents than originally described in package inserts and to consider this new understanding when dispensing atypicals to patients.

OBJECTIVES

After completing this lesson, the practitioner should be able to:

Recognize the differences between patient populations in
rigorous registration studies and those in the typical clinic setting;
Compare and contrast pharmacokinetic differences between atypical antipsychotics and how they may relate to each drug's efficacy, safety, and dosing profiles;
Describe current recommendations of lower dosing of atypical antipsychotics in the treatment of schizophrenia as compared to the labeled dose; and
Describe currently available evidence for dosing recommendations in special populations.

Antipsychotic drug treatment has been available since the 1950s. Despite this, many individuals with schizophrenia remain treatment-refractory, while others achieve remission from only a fraction of their symptoms or relapse from remission after a short amount of time. The fulfillment of social roles of those with schizophrenia is limited, and their rates of relapse, rehospitalization, and suicide remain high, all of which add to an already heavy social and economic impact.¹ Based on the efficacy of therapies in drug registration trials, relapse rates might be expected to be a half to a third of their current rates. One of the most commonly cited reasons for the poor outcome is inadequate compliance. Clinical practice surveys show compliance rates that are much lower than those in controlled clinical trials, with over 30% of treated patients having serious adherence problems.² One significant factor in poor compliance is a lack of tolerability, including well-known side effects such as extrapyramidal symptoms (EPS), particularly akathisia and neuroleptic dysphoria.^1,3 Other factors include lack of insight, substance abuse, and inadequate continuity of care. However, medication tolerability is one factor over which health care providers can have some control. By selecting a treatment with a profile most suitable to the individual patient, the provider can improve compliance as well as outcome. As providers evaluate available clinical data to better understand profiles of current therapies, dose selection becomes an important methodological issue.⁴

Clinical trials, especially those designed to achieve drug registration approval, assess medications in settings that are not truly “real world.” These registration trials are designed to demonstrate optimal efficacy of the drug under study in an acute situation and, therefore, have many restrictions. One main difference relates to the patients being treated. For clinical trials, recruited patients usually not only meet the DSM-IV diagnosis being studied but are also chronically impaired, hospitalized, and often partly drug resistant. These characteristics often lead to higher therapeutic doses to reach efficacy. In addition, registration trial patients typically do not have any comorbid or secondary disorders that meet DSM-IV criteria, and they measure up to minimal health and cognitive status standards, suggesting that higher doses may be better tolerated. In contrast, patients who come into the clinic for treatment of schizophrenic symptoms may be taking other psychotropic medications for comorbid disorders or may have poorer health status, which lowers their threshold for antipsychotic-related side effects. Because of this, drug dosages recommended by these trials are not always optimal for patients encountered in day-to-day practice.⁵

The following is a review of current information regarding the mechanism of action, efficacy, and safety profiles of the most recently approved (US) class of antipsychotic medications often referred to as “atypicals”: clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. In addition, currently recommended dosing guidelines are presented for the treatment of schizophrenia.

Patients with schizophrenia present with a constellation of symptoms that are described as “positive,” “negative,” and “cognitive” symptoms (Table 1).⁶ Positive symptoms consistently include delusions, hallucinations, disorganized thinking, and agitation. Inappropriate emotional responses, pacing, physical preoccupations, depersonalization, and derealization are also positive symptoms; however, they present less frequently. While positive symptoms are the hallmark of schizophrenia, it is the negative symptomatology, ie, lack of drive, social withdrawal, emotional unresponsiveness, and decreased speech fluency, that usually appears first. Cognitive symptoms, including problems with visual processing, attention, executive function, and working memory, do not present as consistently. They tend to vary from person to person, as well as over the course of the disease for an individual. Due to this variability, not all experts agree that cognitive dysfunction is a separate class of symptoms and, therefore, antipsychotic medications have not been reliably tested for efficacy in attenuation of cognitive symptoms. In addition, two other symptom dimensions exist for schizophrenia. These are aggressive symptoms such as hostility, abusiveness, and impulsiveness, and depressive/anxious symptoms such as depressed mood, irritability, worry, and guilt.

Treatment for schizophrenia includes medication for symptom relief and relapse prevention, psychosocial intervention for coping skills and relapse prevention, and reintegration, which helps patients in remission to reenter the community. A combination of these three modalities may enhance treatment response more than any one individually.⁷ Conventional antipsychotics such as haloperidol, chlorpromazine, and fluphenazine only target positive symptoms, and their effectiveness is reduced by extrapyramidal side effects. The newer antipsychotics, the “atypicals,” reduce both positive and negative symptoms, may improve cognitive function, and have a lower frequency of extrapyramidal symptoms. For these reasons, most of the atypical antipsychotic agents—risperidone, olanzapine, quetiapine, and ziprasidone—have replaced the conventionals as the first-line treatment for the management of psychoses. Clozapine, the first atypical agent to be marketed, has a risk of agranulocytosis that excludes it from being used as first-line treatment.

The following dosing information is based on the most recent version of the package insert for each medication.

Clozapine was introduced in 1975 as the first atypical antipsychotic for use in treatment-resistant schizophrenia. Its efficacy was established in a 6-week study comparing it to a conventional antipsychotic, chlorpromazine, in patients resistant to standard drug treatment.⁸ Patients were flexibly titrated during the first 2 weeks up to a maximum dose of 500 mg/day on a TID basis. Dosing for the remainder of the study was maintained in a total daily dose range of 100-900 mg/day on a TID basis, with clinical response and adverse effects as guides to correct dosing. The mean and median clozapine doses in this study were approximately 600 mg/day.

On the basis of the registration studies, the recommended target dose of clozapine is 300 to 450 mg/day given in divided daily doses.⁸ The package insert suggests that dosing begins at 12.5 mg (one-half tablet), increasing daily in increments of 25 to 50 mg/day. If the dose increments are well tolerated, the target dose should be reached by the end of 2 weeks. If the target dose is not effective, the dose may be increased up to a maximum of 900 mg/day while monitoring clinical response and tolerability. To decrease the risk of hypotension, seizure, and sedation, however, dosing should be continued in divided daily doses, subsequent dosage increments should be made no more than once or twice weekly, and each increment should not exceed 100 mg. Rapid dose increases can cause EEG changes that lower the seizure threshold in a dose-dependent manner and may necessitate dose reductions and, if necessary, the initiation of concomitant anticonvulsant treatment. Finally, because of the risk of agranulocytosis and seizures, patients who have reached the maximum dose of 900 mg/day (or a lower maximally tolerated dose), but have not demonstrated an acceptable clinical response, should discontinue treatment.

To discontinue treatment, a gradual dose reduction is recommended over 1 to 2 weeks. If discontinuation is abrupt, the patient should be monitored for symptoms related to cholinergic rebound such as headache, nausea, vomiting, and diarrhea.

Risperidone was the second atypical antipsychotic introduced to the US market. The efficacy of risperidone in the treatment of psychotic disorders was established in four 4- to 8-week trials of psychotic inpatients meeting DSM-IIIR criteria for schizophrenia. In these studies, risperidone was administered on either a BID or QD schedule and was flexibly titrated up to 10 mg/day in one study, while fixed doses of 1, 2, 4, 6, 8, 10, 12, and 16 mg/day were evaluated among the three remaining studies. Efficacy was demonstrated at all doses for psychotic symptoms and overall clinical impression ratings. Doses of at least 4 mg/day were necessary to observe significant improvement in negative symptomatology and doses above 6 mg/day in most studies did not appear to provide additional therapeutic benefit while increasing the risk for EPS and other drug-related adverse events.

Based on these registration studies, a starting dose of 1 mg/day was recommended, increasing to 3 mg/day in 1 mg increments within the first 3 days. Dosing can be administered either as a divided daily dose or as a single daily dose. Further dose increases are recommended in 1 to 2 mg steps and at 1 week or longer intervals. Dosing up to 8 mg/day is suggested to possibly enhance efficacy, and the maximum recommended daily dose is 16 mg/day.

Olanzapine was launched in 1996 and its efficacy for use in patients with schizophrenia was established in two 6-week, fixed dose, double blind studies comparing olanzapine versus placebo.^9,10 Four dose ranges of olanzapine were evaluated in the registration studies: 1 mg/day and 10 mg/day in one study; and 5(+/-2.5) mg/day, 10(+/-2.5) mg/day, and 15(+/-2.5) mg/day in the second study. Both the 10 mg/day and 15 mg/day doses showed superior efficacy to placebo. With the exception of a negative symptom rating scale (SANS) in which only the 15 mg/day dose was superior to placebo, there was no clear advantage for the highest dose over the 10 mg/day dose.¹⁰

Based on these studies, 10 mg/day is recommended as the starting and target dose for olanzapine, administered as a single daily dose. If dosing is started at 5 mg/day, the dose should be increased to 10 mg/day in a few days. Further dose adjustments are recommended to occur at no less than 1 week intervals and in 5 mg increments with a maximum dose of 20 mg/day. As 15 mg/day was not determined to be more efficacious than 10 mg/day, any dose increases above the target dose are suggested only after clinical assessment.

The efficacy of quetiapine in the treatment of schizophrenia was established in three 6-week trials of inpatients with schizophrenia.¹¹ Among the three trials, fixed daily doses of 50 mg, 75 mg, 150 mg, 250 mg, 300 mg, 450 mg, 600 mg, and 750 mg were evaluated. In most studies, administration of quetiapine was on a QID schedule and in one study a comparison of efficacy was done between QID and BID administration with the 450 mg/day and 50 mg/day dose. The lowest dose providing improvement in positive symptoms and overall clinical impression in comparison to placebo was 150 mg/day, while improvement in negative symptoms was achieved at the 300 mg/day dose. Doses up to 750 mg/day provided significant improvement, and safety was demonstrated at up to 800 mg/day; however, the increase in benefit with doses higher than 300 mg/day was not always clear.

Based on these studies, quetiapine dosing is suggested to start at 50 mg/day, administered as a divided daily dose.¹¹ Up-titration is recommended daily in 25 to 50 mg BID or TID increments, up to a target dose range of 300 to 400 mg/day by the fourth day of dosing. Further dose increases, if needed, should occur at least 2 days apart in increments of 25 to 50 mg BID.

The efficacy of ziprasidone in the treatment of schizophrenia has been shown in four acute (two 4-week and two 6-week) trials and one long-term (52-week) trial of inpatients with schizophrenia.¹² Among the five trials, fixed daily doses of 10 mg, 40 mg, 80 mg, 120 mg, 160 mg, and 200 mg, given in divided doses BID, were evaluated. The lowest dose providing significant improvement compared to placebo in positive symptoms and overall clinical impression in comparison to placebo was 40 mg/day, while improvement in negative symptoms was achieved at doses of 80 mg/day and higher. Doses up to 200 mg/day provided significant improvement; evidence for a dose-response across the 40 mg/day to 200 mg/day was not found.

Based on these studies, ziprasidone dosing is suggested to start at 20 mg/day and can be increased up to a maximum of 160 mg/day, depending upon individual patient response.

Atypical antipsychotics have a pleiotropic (ie, producing many effects) pharmacology affecting dopaminergic, serotonergic, adrenergic, and muscarinic activities. Serotonin-dopamine interactions define antipsychotic medications as serotonin-dopamine antagonists (SDA). SDAs are considered atypical antipsychotics because of a relatively low incidence of EPS; reduced rates of tardive diskinesia; fewer increases in prolactin levels, especially compared to haloperidol; greater improvement in negative symptoms than placebo or haloperidol; and efficacy in patients refractory to conventional antipsychotic treatments.

Initially, the atypicals were thought to be similar in their effect at the various receptors and, therefore, in their efficacy and safety profiles. Results of recent studies have shown, however, that each of the five currently available atypicals has a slightly different profile for binding to the receptor sites and that their affinity can also vary with the dose.

Dopamine binds to at least five pharmacologically distinct postsynaptic receptor subtypes in the brain. Antagonism of the dopamine type 2 (D₂) receptor is believed to account for the antipsychotic action of the conventional medications in schizophrenia and may provide a partial explanation for the action of the atypical medications. D₂ blockade also accounts for many of the side effects of both conventional and atypical antipsychotics, as described below.

There are four dopamine pathways in the brain and much of the efficacy and tolerability of typical and atypical medications is related to the relative activation of these pathways. These pathways are depicted in Figure 1.

Dopamine and efficacy—The mesolimbic pathway (pathway 2 in Figure 1) extends from the tegmentum to the nucleus accumbens and is thought to function in arousal, memory, stimulus processing, and motivational behavior. Given these functions, it is suggested that the mesolimbic pathway is integral to behaviors such as the euphoria of drug abuse and sensations of pleasure, as well as the formation of psychosis-related delusions and hallucinations. Antagonism of D₂ receptors along this pathway attenuates the presentation of positive symptoms.

The mesocortical pathway (pathway 3 in Figure 1) projects from the tegmentum to the limbic cortex and is thought to function in cognition, communication, social function, and response to stress. This pathway may mediate both positive and negative symptoms of psychosis. Antagonism of D₂ receptors in this pathway could be responsible for treatment-related cognitive side effects.

Dopamine and tolerability—The dopamine nigrostriatal pathway (pathway 1 in Figure 1) projects from the substantia nigra to the basal ganglia and is responsible for body movements. Antagonism of D₂ receptors in the basal ganglia would lead to increased side effects such as EPS.

The tuberoinfundibular pathway (pathway 4 in Figure 1) projects from the hypothalamus to the anterior pituitary gland and plays a role in controlling prolactin secretion. Antagonism of this pathway would lead to a decrease in inhibition of prolactin release and a subsequent increase in prolactin levels.

D₂ receptor occupancy and antipsychotic efficacy—Antipsychotic efficacy, whether it be due to conventional or atypical medications, seems to be related to the extent of D₂ receptor blockade. Various studies have shown that the optimal balance between efficacy and D₂ receptor-related side effects occurs with 65% to 80% D₂ receptor occupancy. Higher percentages of receptor occupancy are associated with side effects such as elevations in prolactin, EPS, and akathisia. Clinicians may be better able to match antipsychotic therapy with patients by increasing their understanding of each drug's relative blockade of D₂ receptors.

Conventional antipsychotics are most often described as acting solely on the dopaminergic system and having indistinguishable efficacy, which is related to the similar level of D₂ receptor occupancy across medications. In addition, while the conventionals should provide effective treatment, the extent of symptom improvement relates only to positive symptoms, and side effects are significant enough to be treatment-limiting. This is further supported by the fact that conventionals have very high levels of D₂ receptor occupancy.

While the primarily singular D₂ blockade mechanism of the conventional antipsychotic medications is able to ameliorate the positive symptoms of schizophrenia, including hallucinations, delusions, and disorganized thinking, the conventionals generally do not improve the negative and cognitive symptoms of the disease. In contrast, the atypical antipsychotics have relatively lower affinities for the D₂ receptor and may have greater affinities for other receptor systems implicated in the etiology of schizophrenia. The atypicals can be distinguished from the conventionals and even from each other on this pharmacological basis.

The extent of D₂ receptor occupancy by each antipsychotic is determined by its binding affinity for that receptor, and antipsychotic efficacy can be related to its dissociation rate. Specifically, the faster the medication dissociates or unbinds from the D₂ receptor, the lower the percentage of D₂ receptors that will be occupied by the drug at any one time. The atypical antipsychotics dissociate from the receptor faster than the conventional medications (ie, under 60 seconds for quetiapine compared to 30 minutes for haloperidol), effectively giving them lower D₂ occupancy rates.¹⁴ Within the class of atypicals, quetiapine dissociates fastest from the D₂ receptor, followed closely by clozapine, with slower rates of dissociation for olanzapine, risperidone, and ziprasidone.¹⁵ The varying dissociation rates may explain why the atypicals have differing times to relapse.¹⁴ Patients on quetiapine and clozapine, for example, relapse sooner after withdrawal of treatment than those on other atypicals or the conventionals.¹⁴

If D₂ receptor occupancy were the sole mechanism of atypical antipsychotic efficacy, efficacy profiles would be predictable based on their different D₂ affinities. Randomized controlled trials, however, have not borne this out. Registration studies for atypicals such as risperidone, olanzapine, and quetiapine have shown similar improvements in positive psychotic symptoms in nonrefractory patients. However, patients receiving clinically effective doses of clozapine or quetiapine have been shown to have only transiently high levels of D₂ occupancy that quickly decrease to relatively low D₂ occupancy compared to the higher level of D₂ occupancy found with risperidone.¹⁶ In addition, until recently, clozapine was the only atypical to show efficacy in treatment-refractory patients. A recently completed study of quetiapine in over 500 patients also showed improvement in both positive and negative symptoms.¹⁷ Subsequent research has suggested that atypical antipsychotics may achieve their effectiveness through occupancy of other neurotransmitter receptors, such as 5-HT₂, or selective activity in differing brain regions.

While the responsible receptor system or systems is not clearly defined, atypicals have demonstrated improvement in several domains of cognitive functioning in schizophrenic patients (Table 2). A review of clozapine, risperidone, and olanzapine data by Meltzer and McGurk¹⁸ supports their ability to ameliorate the cognitive impairments in schizophrenia. A small double-blind study suggested that quetiapine also improves cognitive function compared to haloperidol.¹⁹ While this phenomenon is not found after treatment with conventional antipsychotics, indicating a mechanism of action other than D₂ blockade, preclinical studies have suggested that dopamine release and dopamine receptors do play a role in the treatment of cognitive symptoms. For example, clozapine has been shown to increase dopamine release in the prefrontal cortex, the brain region implicated in working memory deficits. Further, one of the main dopamine receptor subtypes located in the prefrontal cortex has been found to interact with glutamate receptors, enabling the formation of memories.²⁰

In addition to increasing dopamine levels by antagonizing D₂ receptors, some neuroleptics enhance dopamine by blocking dopamine transporters.²¹ Among the atypical and conventional neuroleptics, ziprasidone has the second highest binding potency for the dopamine transporter, as well as one of the highest potencies for binding to the serotonin and norepinephrine transporters. Clozapine, olanzapine, risperidone, and quetiapine, however, have almost negligible binding potencies for the monoamine transporters.

The rediscovery of clozapine in the late 1980s brought about a new era in treating the symptoms of schizophrenia. In addition to positive symptoms, clozapine had the added benefit of treating negative and cognitive symptoms, which had an even greater effect on patients' quality of life. As clozapine was known to be an agonist at serotonin receptors, clinical development of antipsychotic medications turned to exploiting the action on serotonin in addition to dopamine. Like dopamine, serotonin is released and distributed throughout the brain via multiple pathways. These pathways control the antidepressant, cognitive, movement-related, emotional, sexual, and appetite effects of serotonin.

Serotonin-dopamine interactions—Both the serotonin and dopamine systems have projections to the basal ganglia as described above. Terminals of the dopamine-containing neurons in the basal ganglia and the anterior pituitary gland have presynaptic serotonin receptors, specifically 5-HT_2A. In both the nigrostriatal pathway and the tuberoinfundibular pathway, dopamine release is regulated by serotonin. If serotonin is not able to bind the 5-HT_2A receptor, dopamine will be released. This means that even in the presence of a D₂ antagonist, fewer EPS would be expected. Similarly, in the tuberoinfundibular path, prolactin levels would not be increased as much. An excess of serotonin in the mesocortical pathway may lead to secondary dopamine deficiency in this area, exacerbating the negative symptoms of schizophrenia and, hence, antagonism of the 5-HT_2A receptors is suggested to improve negative symptoms.

In addition to binding at the 5-HT_2A receptors, several of the atypicals bind to 5-HT_2C receptors and 5-HT_1A receptors, which are also implicated in the etiology of schizophrenia. A recent study by Newman-Tancredi et al²² examined the binding of 15 antipsychotics, including several atypicals, to human 5-HT_1A receptors expressed in vitro. In competitive-binding experiments, ziprasidone and quetiapine displayed properties consistent with agonist actions, and clozapine binding was consistent with its action as a partial agonist at 5-HT_1A receptors. The conventionals haloperidol, chlorpromazine, and thioridazine, on the other hand, displayed binding properties suggestive of an inverse agonist. (NOTE: Whereas an antagonist binds to the receptor and blocks the agonist effect, an inverse agonist binds to the receptor and produces an opposite effect.) Olanzapine and risperidone had binding properties in between that of the conventionals and quetiapine and ziprasidone. This pharmacological differentiation of agonist versus inverse agonist properties of antipsychotics at 5-HT_1A receptors may contribute to differing profiles of antipsychotic activity, such as the alleviation of depressive symptoms demonstrated by ziprasidone or anxiolytic effects (5-HT_2C).¹⁵

Initially, the therapeutic advantage of atypical antipsychotics was thought to be due to alpha-2-adrenergic antagonist effects.²³ However, of the five marketed atypicals, only clozapine, risperidone, and quetiapine have been shown to have affinity for binding the alpha-2 receptors. More recently, research has implicated both cholinergic and glutamatergic neurotransmitter system dysfunction in schizophrenia and its treatment.^24,25

Approximately 10% of the population has a genetic mutation in nicotinic acetylcholine receptors that has been associated with difficulties in sensory gating and the impaired cognition and psychosis seen in schizophrenia. Studies have implicated the alpha-7 subtype of the nicotinic receptor²⁴ in this function, and the efficacy of several atypicals in improving cognitive symptoms may derive from their ability to effect nicotinic receptor transmission.²⁶

Competitive blockers of the NMDA receptor, a subtype of glutamate receptor relevant to memory and learning processes, have been used to model the pathophysiology of schizophrenia.²⁵ Blocking the NMDA receptor can cause perceptual disturbance and cognitive dysfunction similar to that seen in patients diagnosed with schizophrenia, as well as altered regional cerebral blood flow in brain areas affected by schizophrenia. Specifically, positron-emission tomography (PET) studies have shown that NMDA receptor blockade decreases blood flow in the hippocampus and cerebellum, while increasing blood flow in the anterior cingulate cortices.²⁵ This role of glutamate receptors may be relevant to atypical antipsychotic action in the prefrontal cortex. As previously mentioned, atypicals have been shown to increase dopamine release in this region, indicating that dopamine receptor activity may be increased and their interaction with glutamate receptors may be increased.²⁰ Enhanced glutamate receptor activity could lead to improvement in cognitive symptoms. Additional study is needed to begin unraveling this complicated story.

The lower rate of several clinically important side effects is one of the most salient advantages of the atypicals. In addition to the possible advantage of reducing negative symptoms and improving cognition, atypicals may also have a more tolerable side effect profile leading to better patient compliance. While the atypicals are more tolerable, they still have side effects that must be considered when weighing treatment options for the individual patient. These side effects include weight gain, diabetes mellitus, prolactin elevation, and extrapyramidal side effects.

Weight gain associated with many antipsychotics is one of the side effects cited for poor treatment compliance, and it may precede more serious health complications such as diabetes, cardiovascular disease, and certain types of cancer. Clozapine and olanzapine are the atypical antipsychotics most likely to cause weight gain, the average being approximately 10 lb. Risperidone has been associated with intermediate levels of weight gain (approximately 5 lb), while ziprasidone and quetiapine have been associated with the least.^27,28These observed increases in weight were demonstrated in short-term trials. The extent of total weight gain may be much greater with chronic use, but this needs to be explored further.

Individuals with schizophrenia are at greater risk of developing type 2 diabetes than the general population, and this predisposition can be exacerbated by the introduction of antipsychotic medication.²⁹ The effect is exemplified by a significant increase in case reports for new-onset or exacerbated diabetes, hyperglycemia, or ketoacidosis associated with the greater use of atypical antipsychotics. A total of 37 incidents were reported in the literature through June 2000; the majority indicate that hyperglycemia and ketoacidosis appear in a relatively short time after initiation of atypical antipsychotic treatment, and that events are resolved after treatment discontinuation only to re-emerge with rechallenge.³⁰ Suggested causes include weight gain, dysregulation of glucose metabolism, and development of insulin resistance. Olanzapine and clozapine, both more likely to induce weight gain than other atypicals, have also been more highly associated with an increased risk for diabetes and diabetic ketoacidosis (Figure 2).³¹A recent population-based case-control study evaluating over 19,000 patients with schizophrenia, for example, found that olanzapine significantly increased the risk of developing diabetes compared to patients who did not take antipsychotic medication as well as those who took conventional antipsychotics. In comparison, patients treated with risperidone had a nonsignificantly increased risk of developing diabetes compared to those taking conventional antipsychotics or nonusers.⁵²

Individuals with schizophrenia are also at increased risk relative to the general population for developing tardive dyskinesia (TD), which is involuntary stereotypical movements that occur after prolonged dopamine blockade. Risk for this irreversible event is even greater in those with mood disorders, EPS, and diabetes, which are all associated with schizophrenia or its pharmacological management. The risk for TD is lower with risperidone and olanzapine treatment than with haloperidol, and research indicates that lowering the dose of the antipsychotic treatment and/or replacing conventional treatment with atypical treatment may decrease rates of TD.^13,32,33

Advances in imaging techniques have allowed the relationship between receptor occupancy and side effects of antipsychotic medication to be demonstrated in humans.³⁴ Positron-emission tomography (PET) and single photon emission computed tomography (SPECT) studies have consistently demonstrated D₂ receptor occupancy of greater than >65-70% in patients being treated with antipsychotic drugs. Imaging has also shown that when D₂ receptor occupancy increases above 80%, patients have a much higher risk of EPS, suggesting better tolerability with therapies that achieve a D₂ receptor occupancy of 80% or below.

As a class, the atypical agents have a relatively low incidence of EPS and TD, and the reason appears to be their lower affinity for the D₂ receptor. Similarly, prolactin elevations, which occur when dopamine receptors are antagonized and prolactin becomes disinhibited, are less frequent with atypical treatment than conventional treatment. As discussed in the mechanism of action section, the faster the drug dissociates from the D₂ receptor, the lower the rates of these treatment-emergent side effects. Thus, clozapine and quetiapine predictably have the lowest side-effect rates; while the rates are higher with olanzapine and risperidone, they are still significantly lower than with haloperidol and chlorpromazine.

The dopamine-related side effect profiles of some atypicals are dose-dependent, however, and can begin to resemble those of the conventionals as doses are increased. For olanzapine, risperidone, and ziprasidone, increasing dosage raises relative D₂ occupancy. If the dose is increased sufficiently to achieve D₂ receptor occupancy similar to that achieved by standard doses of haloperidol, the risk of EPS also becomes similar to haloperidol. Risperidone, which at higher doses (above 6 mg/day) is the atypical most similar to conventional antipsychotics in terms of D₂ receptor occupancy, is the atypical most likely to cause an increase in serum prolactin levels. This side effect, however, becomes clinically important only when accompanied by galactorrhea, gynecomastia, and amenorrhea, which may lead to decreased bone mineral density. Clozapine and quetiapine, on the other hand, are unable to block more than 70% of D₂ receptors and are not associated with dose-dependent increases in risk for EPS or prolactin elevation.

While clozapine is highly efficacious, it is the most pharmacologically complicated, with binding affinity for D₁, D₄, muscarinic, and alpha-adrenergic receptors, in addition to D₂ and 5HT₂ receptors.⁸ This profile gives clozapine the potential for treatment-emergent agranulocytosis, seizures, and anticholinergic effects, making it more restrictive to use than other atypicals; it is not recommended for use as a first-line agent for schizophrenia.

The relationship between tolerability and effectiveness is important for all of the atypicals, and understanding each drug's profile may help determine the best pharmacological agent for an individual patient.³⁵ Differences in side effect profiles may have implications for effectiveness, and the side effect profile may be dependent upon the dose administered. As a result, finding the optimal dosing regimen for these medications (ie, D₂ occupancy <70%, increased serotonin effects, etc.) may determine their ultimate effectiveness. As an example, both risperidone at doses higher than 4 mg/day and olanzapine at doses higher than 20 mg/day are associated with an increased risk of treatment-emergent EPS. At these higher doses, patients are less likely to be treatment compliant, rendering treatment less effective.

Finally, not all adverse events seem to be dose-related, even when highly associated with one or more of the antipsychotic medications. EEG abnormality is one such adverse event. The increased risk of EEG abnormalities was evaluated in more than 300 psychiatric inpatients, the majority of whom received treatment with either atypical or conventional antipsychotics.³⁶ The percentage of patients who had EEG abnormalities was greater in those treated with antipsychotics (19% versus 13%), and the risk varied significantly by drug type (clozapine=47.1%, olanzapine=38.5%, risperidone=28.0%, typical neuroleptics=14.5%, quetiapine=0.0%). In contrast, risk was not associated with drug dose (in mg or mg/kg), drug exposure, or drug potency.

PET studies conducted in monkeys demonstrate D₂ receptor occupancy ranges of 54% to 58% after a dose corresponding to approximately 210 mg/day in humans and increases to 87% to 89% at the equivalent of 2800 mg/day in humans.^37,38 These studies demonstrated that sufficiently high doses of clozapine can completely saturate D₂ receptors within a relatively short time, while standard doses of clozapine produce relatively low D₂ receptor occupancy.

Clozapine remains a second-line therapy for schizophrenia; however, it is still considered the “gold standard” for treatment-refractory patients.³⁹ While superior efficacy of clozapine was found at doses between 300 and 900 mg/day, higher doses are associated with seizures at a rate of 5%.

Two Cochrane reviews evaluated the effectiveness of risperidone with respect to conventional antipsychotics⁴⁰ and to other atypical antipsychotics.⁴¹ All randomized trials comparing risperidone and conventional medications or risperidone and other atypicals were included.

A total of 3401 patients were included among the 14 studies with comparisons to conventionals; however, this survey only included data available through 1997.⁴⁰ The review showed that risperidone, in comparison to conventional medication, increased the odds of moderate clinical improvement, had a decreased incidence of movement disorders as measured by the concomitant dosing of antiparkinsonian medication, had fewer dropouts, and fewer episodes of somnolence. This is in concordance with many of the results from the registration studies described above. Similar to the other atypicals already described, however, risperidone increased the likelihood of patients gaining weight while on treatment. Looking at effectiveness of risperidone by dose in comparison to the conventionals, the sensitivity analyses were unable to show any relevant differences, most likely because doses of 2 mg and below were excluded from the analysis and most studies included in the literature review had mean doses higher than currently recommended. A review of short-term, large, controlled trials also showed that risperidone was more beneficial than conventional medications in terms of both positive and negative symptoms.⁴²

A Cochrane review was also conducted of studies comparing risperidone to other atypicals.⁴¹ This review included nine studies, 466 patients among five studies in comparison with clozapine, 400 patients among three studies in comparison with olanzapine, and 228 patients in a single study with amisulpride (not available in the United States). These studies, like the ones previously cited, included a majority with dosing higher than current recommendations. In fact, the review cited the higher than recommended doses as a possible reason for a difference in the incidence of EPS between olanzapine and risperidone. All other measures had large confidence intervals and judgments could not be made.

Risperidone may have shown even greater effectiveness in treating schizophrenia and other schizophrenia-like illnesses if the more recent, lower dosing recommendation had been used. Indeed, more recent preclinical and clinical studies suggest that lower doses may improve tolerability without decreasing efficacy and overall may enhance the antipsychotic effectiveness of the medication.³²

A PET study evaluating the minimal effective dose for risperidone, while correlating D₂ and 5-HT_2A receptor occupancy, for example, found that the D₂ receptor occupancy after administration of risperidone to schizophrenic patients is dose-dependent.³² At the previously recommended standard dose of 6 mg/day, mean D₂ receptor occupancy was in the range of 79% to 85%. This range is similar to most conventional antipsychotics, and a majority of the patients developed EPS. When the dose was reduced to 3 mg/day, D₂ receptor occupancy was in the range of 53% to 78%, and fewer patients had EPS. In contrast, 5-HT_2A receptor occupancy was not found to be dose-dependent, with a mean occupancy of 95% and 83% at the high and low dose, respectively. These data suggest that risperidone treatment at 6 mg/day induces unnecessarily high D₂ receptor occupancy and an increased risk of EPS. As discussed under mechanism of action, an optimal interval for D₂ receptor occupancy is approximately 65% to 80%, which could be achieved by a 4 mg/day dose of risperidone.

In addition, a thorough review of risperidone data, clinical audit, phase 4 trials, and PET data found that 4 mg/day, rather than 6 mg/day, was the most effective target dose for adult schizophrenic patients.⁵ A less-rapid titration than previously recommended was also found to be more beneficial. Moreover, a dose lower than 4 mg/day and slower titration may be appropriate for elderly patients, young patients, and first-episode patients.

Included in the review above were several head-to-head trials evaluating both efficacy and tolerability profiles of risperidone in comparison to haloperidol or other atypical antipsychotics. These studies, in contrast to the registration trials, used either flexible dosing or a fixed dose lower than currently recommended in labeling. In one study, adult outpatients in stable condition with chronic schizophrenia or schizoaffective disorder were randomly treated with risperidone or haloperidol for a minimum of 1 year.⁴³ Relapse rates were compared between the two treatment groups as a measure of efficacy. Three hundred and ninety-five patients were evaluated after the completion of double-blind treatment. The allowable dose range in this flexible dose study was lower than previous guidelines suggested. The dose range for risperidone was 2 mg/day to 8 mg/day with a mean modal dose of 4.9 mg/day; the dose range for haloperidol was 5 mg/day to 20 mg/day with a mean modal dose of 11.7 mg/day. Patients who received treatment with risperidone remained in treatment for a significantly longer time than those treated with haloperidol (364 days versus 238 days, respectively; p=0.02). The longer duration of treatment appeared to be driven by the lower relapse rates with risperidone; the Kaplan-Meier estimate of the risk of relapse after risperidone was almost half that of haloperidol (34% versus 60% respectively; p<0.001). Risperidone also brought about greater reductions in the mean severity of both psychotic symptoms and EPS compared to those in the haloperidol group.

Risperidone efficacy and tolerability were also compared to another atypical, olanzapine, in a randomized, double blind trial of patients with schizophrenia or schizoaffective disorder.⁴⁴ In contrast to two previously conducted trials also directly comparing risperidone and olanzapine,^45,46 the doses chosen for risperidone were those widely accepted in clinical practice rather than those studied in registration trials. The dose range for risperidone was 2 to 6 mg/day, and the mean modal dose was 4.8 mg/day. For olanzapine, the dose range was 5 to 20 mg/day, and the mean modal dose was 12.4 mg/day. At the end of the 8-week treatment period, no differences were seen in rate of dropout or EPS and both groups had significant reductions in positive and negative symptoms as measured by the Positive and Negative Symptom Scale (PANSS). The only significant differences in efficacy measures between the groups were greater reductions in the severity of positive and affective symptoms after risperidone treatment compared to olanzapine. Consistent with olanzapine literature, more than twice as many olanzapine-treated patients had clinically important increases in body weight during the study compared to risperidone-treated patients.

In summary, the original target dose of risperidone recommended for the treatment of schizophrenia appears to be too high for most patients. Instead, in order to achieve the optimal balance between efficacy and tolerability, it is recommended that a daily dose in the range of 2 to 4 mg/day be used in the treatment of nonelderly adults with schizophrenia.

In a Cochrane review,³³ 20 randomized clinical trials were used to evaluate the effectiveness of olanzapine in comparison to placebo, other atypicals, and conventional antipsychotics. Extensive patient attrition (>61%) made the interpretation of results difficult. The review found data regarding attenuation of negative symptoms equivocal in the placebo controlled trials, while in comparison to the conventionals, olanzapine had better PANSS total scores as well as positive and negative symptom subscores. In safety measures, a lower incidence of EPS was found with olanzapine treatment compared to haloperidol treatment, while weight gain results were inconclusive. Similar to the risperidone review, few differences were found in comparing olanzapine to other atypicals.

Included in the above review were several head-to-head trials that evaluated both efficacy and tolerability profiles of olanzapine compared to haloperidol or other atypical antipsychotics. In a multi-national, double blind, 6-week trial, a total of 1996 patients were randomly assigned to treatment with olanzapine or haloperidol.⁴⁷ Efficacy was evaluated on the Brief Psychiatric Rating Scale (BPRS), positive and negative symptoms, comorbid depression, extrapyramidal symptoms, and overall drug safety. Similar to other atypical study results, olanzapine was also associated with significantly fewer discontinuations of treatment, and more olanzapine-treated patients completed the full 6 weeks of therapy than haloperidol-treated patients (67% versus 47%, respectively). In terms of efficacy, patients treated with olanzapine at the 10 mg/day dose had significantly greater reductions in negative symptoms than haloperidol-treated patients, and there were significantly more treatment responders. Overall, olanzapine treatment provided greater improvement on all measures of efficacy evaluated. The tolerability of olanzapine was also shown to be better than haloperidol in that there were significantly fewer EPS or increases in prolactin levels.

In registration studies, only the 10 and 15 mg/day doses provided superior efficacy, and there was no clear advantage for the 15 mg/day dose over the 10 mg/day dose. The 20 mg/day dose was not tested for efficacy in these studies. Postregistration studies, however, have evaluated higher doses of olanzapine and suggest that doses above 15 mg/day can provide greater efficacy for some patients without compromising tolerability, especially if agitation is present. In the treatment of women with schizophrenia, however, clinicians need to be aware that plasma levels can be higher than in men at comparable doses, suggesting that women may require lower doses. Additionally, smokers may require increased doses due to induction of cytochrome P450 1A2 enzyme.⁴⁸

The effects of quetiapine on D₂ and 5-HT_2A receptor systems have been explored in schizophrenic patients in PET imaging studies.^16,49 After random assignment to quetiapine doses ranging from 150 to 750 mg/day for up to 4 weeks, the relationship between plasma concentrations and D₂ and 5-HT_2A receptor occupancy was evaluated. Results show that quetiapine gives rise to transiently high (58%-64%) D₂ occupancy after a single dose, which then decreases to very low levels by the end of the dosing interval (0%-41%). On the other hand, quetiapine can induce a consistently higher degree of 5HT_2A receptor occupancy (up to 74%). With these very low levels of D₂ occupancy and higher 5-HT_2A occupancy, quetiapine was able to improve psychotic symptoms without inducing EPS or increasing prolactin levels. In most cases, quetiapine even resulted in a reduction of baseline level EPS and prolactin elevation.¹⁶ While earlier studies suggested the involvement of other neurotransmitter systems in the reduction of positive symptoms, these data indicate that transiently high D₂ occupancy may be sufficient for quetiapine's antipsychotic effect.

Clinical trials suggest a dosing range between 150 and 750 mg/day, most often dosed on a TID regimen, for effective treatment of schizophrenia. Clinical practice, however, indicates that patients are more frequently dosed between 300 and 400 mg/day on a BID regimen, even going to a QD regimen during maintenance treatment when the dose is below 400 mg/day. With the relatively tolerable side effect profile, increasing the dose to improve efficacy is indicated. In an open-label extension trial, for example, >65% of the patients were on doses between 400 and 800 mg day, suggesting an appropriate dose range in chronic adult schizophrenia of 400 mg to 800 mg daily.

Ziprasidone is the most recent antipsychotic available on the market and thus the data on optimal dosing is limited. A review of available literature, however, suggests that the starting dose of 20 mg BID recommended in the package insert may not be sufficient. Three of four acute treatment studies in patients with schizophrenia failed to show superiority of 20 mg BID compared to placebo.⁵⁰ The 40 mg BID and 80 mg BID doses demonstrate robust superiority to placebo and equivalence to haloperidol. In clinical practice, dosing is commonly increased, as tolerated, every 1 to 2 days beyond the 20 mg BID dose to a maximum of 80 BID.⁵¹

While the atypical antipsychotics can achieve predictable levels of symptom improvement, this will depend upon the clinician's assessment of the appropriate medication and dose for their individual patient. The patient's current health status, ie, do they have risk factors for diabetes; their gender; whether he or she is a smoker; their current spectrum of schizophrenia symptoms; and their previous response to antipsychotics agents, will all impact the choice of pharmacological agent and dose. A single, standard atypical antipsychotic dose may only exist for an individual patient.