Original Author: Paul Perry, Ph.D, BCPP
Latest Revisers: Paul Perry, Ph.D, BCPP, Brian C. Lund,
Pharm.D.
Creation Date: 1996
Last Revision Date: October 2001
Peer Review Status: Internally Peer Reviewed
HIGH-POTENCY AND LOW-POTENCY TYPICAL ANTIPSYCHOTICS
When dosing typical antipsychotics they can grossly be divided into two major subdivisions. They include the high-potency antipsychotics and the low-potency antipsychotics. Tables 1 and 2 below compare and contrast the clinical pharmacology of these two groups of agents. Table 1 demonstrates the ability of these agents to block histaminic, adrenergic, and muscarinic receptors after being corrected for clinical dose. Table 2 notes the adverse effects usually associated with the blockade of these receptors (Black and Richelson 1987).
The low-potency antipsychotics, i.e., chlorpromazine, thioridazine, and mesoridazine besides causing the usual anticholinergic adverse effects of dry mouth, urinary retention, constipation and blurred vision are more likely than the high-potency antipsychotics to cause CNS dysfunction, i.e., anticholinergic intoxication. Recent memory loss is probably the most sensitive portion of the mental status of the patient to check for this adverse effect. Since high- potency antipsychotics are more likely to cause extrapyramidal adverse effects, they will require larger doses of the antiparkinsonian agents, i.e., benztropine, trihexyphenidyl, etc. Thus recent memory should be periodically checked to determine whether the exogenous anticholinergic agents, i.e., low-potency antipsychotics and antiparkinsonian agents are having a deleterious effect on the patients mental status. Additionally, the low-potency agents are more likely to cause orthostatic hypotension, which can be particularly disabling to the patients. In favor of the low-potency drugs is their ability to cause fewer extrapyramidal adverse effects but at the cost of excessive intrinsic anticholinergic activity. The other commonly suggested advantage for the low-potency medications is their greater sedative activity. However, experience and clinical studies lead one to conclude that the sedating dose is often times considerably higher than the antipsychotic dose. The end result of utilizing sedating doses of antipsychotic drugs is that patients are given excessive doses thereby increasing their discomfort from the adverse effects of these drugs. A far more rationale pharmacologic practice for sedating patients on antipsychotics is to simply augment their therapy with benzodiazepines.
Certain principles regarding dosage are generally accepted. Historically, antipsychotic doses are increased until therapeutic effects are achieved or intolerable side effects occur. A dose of at least chlorpromazine 300 mg or its equivalent is considered a minimal therapeutic dose for the treatment of acute psychosis (Davis and Casper 1977, Davis 1974). As a general rule, an individual entering the hospital with psychosis that is not uncontrollably agitated can be started on chlorpromazine 100 mg or its equivalent (i.e., about 1.5 mg of haloperidol) on a BID schedule. The medication is gradually increased at the rate of chlorpromazine 100-200 mg/d until the maximal therapeutic effect or intolerable side effects occur (Davis and Casper 1977, Davis 1974). The maximum daily dose of thioridazine is 800 mg because of the possibility of pigmentary retinopathy (Davis and Casper 1977, Davis 1974). One week after a stable dose is achieved the medication should be given once daily, usually at bedtime. This dogmatic dosing approach is still required of the phenothiazines but may not necessarily be a requirement for the dosing of butyrophenones. Currently, the authors have found that haloperidol is well-tolerated when dosed into its therapeutic range (8-18 ng/ml) However, patients receiving higher doses often require prophylaxis for extrapyramidal side effects with benztropine 2 mg/d and propranolol 40 mg/d.
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Table 1. The pharmacologic profile for the high and low-potency antipsychotics where 1+ is least and 3+ is the most. |
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Chemical Class (example) |
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Blockade |
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Phenothiazine |
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piperidine |
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piperazine |
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Butyrophenone |
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Thioxanthene |
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Dihydroindolone |
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Dibenzoxazepine |
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Dibenzodiazepine |
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Table 2. Adverse effects caused by blockade of muscarinic, histamine H1, and a1-adrenergic receptors. |
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Receptor Type |
Adverse Effects |
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Muscarinic |
urinary retention |
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Histamine H1 |
sedation |
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a1-adrenergic |
postural hypotension |
SINGLE DAILY DOSING
Antipsychotic drugs generally have a long biological half-life. The meta-bolism and excretion of these agents proceed at a slow rate. For example, the presence of one dose of chlorpromazine (Thorazine) can be detected in urine for up to four days while its behavioral effects are obvious for eight to twenty- four hours (Hollister 1962, Sugerman and Rosen 1964). These drugs and their metabolites will accumulate in body tissues until saturation equilibrium occurs with continued dosing (Shephard and Wing 1962). When antipsychotics are discontinued after reaching steady state equilibrium, body tissues will release the drug slowly. Traces of active phenothiazine drug or metabolite may be detected in the urine two to three months after discontinuation (Good et al 1958). Thus, because antipsychotic drugs have a long duration of effectiveness, it is irrational to utilize sustained-release dosage formulations such as spansules or chronotabs.
Clinicians have found single daily dosing of typical antipsychotic agents therapeutically equivalent to multiple daily dosing.
Hrushka et al (1966) conducted a double-blind study with 60 chronically psychotic female inpatients (average age = 52.3 years) comparing once daily and tid dosing of chlorpromazine. The patients were administered either 150 mg or 300 mg per day for five months. The authors found no significant differences among groups with respect to anxiety, affect, socialization, work attitude, appearance, or side effects. They concluded that once-daily dosing could be especially valu-able in noncompliant patients.
Vestre and Schiele (1966) studied a total of 100 inpatients (mean age = 50 years) to compare sustained release and regular thioridazine (Mellaril) on two medication schedules, i.e., thrice daily and single daily dosing. The total daily dosage was 600 mg. Patients were rated before treatment and after four and eight weeks of treatment on the Brief Psychiatric Rating Scale and on a work performance rating scale. Side effects were rated weekly. No significant differences were found between thrice daily dosing and single daily dosing.
Besides improving compliance, administration of the daily dose near bedtime takes advantage of the sedative properties of the antipsychotic. Once daily dosing saves nursing time in passing medications and reduces cost by utilizing larger dosage forms of the drug.
SWITCHING ANTIPSYCHOTICS
When switching a patient from one antipsychotic to another, Table 3 has been constructed to estimate the interdrug milligram potencies of the typical antipsychotic drugs. Davis (1974) constructed the following table by first identifying all the double-blind controlled studies which compared the other antipsychotics to chlorpromazine, the "standard." He then calculated the mean dose of the antipsychotics given to the patients. If unavailable, he approximated the mean dose with the data available in the study. He then calculated the ratio of each antipsychotic to chlorpromazine. If the antipsychotic had never been compared to chlorpromazine but to other antipsychotics previously compared to chlorpromazine, the ratio was determined indirectly. The average dose of chlorpromazine was 734 mg + 63. Thus, if the relative potency value for an antipsychotic is multiplied by a factor of 7.34, the resulting product will be the mean dose reported in the efficacy studies. This is a reasonable prospective estimation of the initial target dose the clinician should aim for when first dosing new acutely ill schizophrenics patients if not utilizing either haloperidol or clozapine blood levels to dose the patient.
ORAL-PARENTERAL DOSE EQUIVALENTS
Oral <--->- IM conversion
Hollister et al (1963) compared the potency of oral and intramuscular (IM) chlorpromazine and thioridazine in two groups of 12 patients. The chlorpromazine and thioridazine groups received either a single 200 mg dose of an oral preparation or 50 mg intramuscularly on a weekly basis. Pulse rate, blood pressure, state of consciousness, and mood changes (Clyde Mood Scale), were assessed at predetermined intervals. It was observed that the 200 mg oral dose of chlorpromazine produced slightly more pronounced changes with the above measurements than the 50 mg IM dose. But these differences were not significant. The authors extrapolated these findings to suggest that the IM dose was about three times as potent as the same amount given orally. In the case of thioridazine, both oral and IM doses (200 mg and 50 mg, respectively) produced comparable clinical changes. Therefore, the potency ratio of intramuscular to oral doses was estimated to be 4 to 1. Thioridazine is not available for injection at this time although its primary metabolite mesoridazine is available as a 25 mg/ml ampule. These data has been extrapolated to the other phenothiazine derivatives that are available for injection, though they have not been specifically studied. These include chlorprothixene, mesoridazine, perphenazine, prochlorperazine, trifluoperazine, and triflupromazine.
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Table 3. Relative antipsychotic potencies among antipsychotic drugs. |
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Antipsychotic |
(mg) |
(mg) |
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Phenothiazines |
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Aliphatic |
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chlorpromazine (Thorazine) |
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triflupromazine (Vesprin) |
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Piperidine |
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thioridazine (Mellaril) |
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mesoridazine (Serentil) |
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Piperazine |
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prochlorperazine (Compazine) |
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perphenazine (Trilafon) |
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trifluoperazine (Stelazine) |
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fluphenazine (Prolixin) |
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acetophenazine (Tindal) |
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butaperazine (Repoise) |
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Thioxanthenes |
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chlorprothixene (Taractan) |
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thiothixene (Navane) |
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Butyrophenones |
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haloperidol (Haldol) |
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Dibenzoxazepine |
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loxapine (Loxitane) |
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Dibenzodiazepine |
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clozapine (Clozaril) |
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Indolone |
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molidone (Moban) |
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Oral haloperidol is approximately 60% bioavailable when compared to intramuscular haloperidol (Bianchetti et al 1980, Forsman and Ohman 1977). Therefore, 5 mg IM is approximately equal to 8 mg po of haloperidol.
Oral to IM Depot
Fluphenazine. Yadalam and Simpson (1988) reviewed the published methods for switching patients from oral fluphenazine to depot fluphenazine decanoate and found the methods to be unacceptable primarily because of the large differences in the blood levels produced by the two drug formulations. Thus, based on their clinical experience they proposed an elaborate dosing schedule that tapers the oral drug while the injectable formulation is titrated upward over a 10 week period. The reason there may be considerable disagreement as to how to switch patients from the oral to the depot form of fluphenazine is best summarized by Johnson's frustrations with this issue. He reviewed the drug regimens of a total of 404 schizophrenics being administered injectable long-acting phenothiazines for periods of 12 to 15 months (Johnson 1975). The data demonstrated there is no universally applicable dosage schedule in maintenance treatment, and each patient's dose per injection and interval between injections must be individualized.
Haloperidol. In a clinical trial comparing intramuscular haloperidol decanoate and oral haloperidol in chronic schizophrenic patients, Nayak et al (1987) found a significant correlation between the monthly dose requirement of haloperidol decanoate and the daily dose of oral haloperidol. The ratio of depot haloperidol to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0. Thus the manufacturer recommends that the initial dose of haloperidol decanoate ought to be 10-15 times the previous daily dose. Using their raw data, we derived the least squares equation:
HLP decanoate (monthly) = 15 (daily HLP) - 7 (eq. 1)
Equation 1 is based on the findings of Nayak et al (1987) in 22 chronic schizophrenic patients. The correlation coefficient for this relationship was 1.00 (p<0.0001). The utility of this formula is obviated by the fact that haloperidol decanoate has approximately a 21-day half-life whereas the oral form of the drug has approximately an 18-hour half-life. Thus patients being directly switched from the oral formulation to the injectable drug will have their blood concentrations become subtherapeutic within a matter of days after the initial injection unless they receive supplemental oral haloperidol. The depot formulation serum concentrations will not be equal to those of the oral drug until steady-state is reached 3 to 4 months later. Thus the patient has an extremely high risk of relapsing. This problem can be circumvented by taking the data of Reyntgens et al (1982) into consideration. They measured plasma haloperidol concentrations in 181 chronic schizophrenic inpatients who received haloperidol decanoate injections every 4 weeks. It was assumed that steady-state levels had been reached after three injections and concentrations were measured just prior to the next injection, (i.e., day 28). The data points were based on the mean haloperidol plasma concentrations corresponding to the 12 discrete doses administered during this period which ranged from 20-350 mg every 4 weeks. The log of the haloperidol plasma levels correlated significantly (r=0.86) with the log of the injected doses of the decanoate formulation according to equation 2 (Reyntgens et al 1982).
haloperidol (ng/ml) = 0.0291 (dose1.047) Eq. 2
Table 4 below shows the steady-state plasma haloperidol concentrations predicted by the relationship.
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Table 4. Projected plasma steady-state haloperidol plasma concentrations expected from haloperidol decanoate |
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(mg/4 weeks) |
Month 1 |
Month 3 |
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One practical method to use Table 1 when switching patients from an oral haloperidol dose to IM haloperidol decanoate is to assume that haloperidol decanoate has a 21-day half-life. Assuming a 21-day half-life for the drug allows one to also assume that the steady-state haloperidol concentration which will take 12 weeks or three 4-week injections to be achieved, will be 1.66 times the first dose's serum concentration drawn on day 28 just prior to the next injection. For example, if a concentration of 9 ng/ml of oral haloperidol is required to control the patient, a reasonable dosing strategy would be to load the patient with haloperidol decanoate 400 mg during the first 4 weeks (Table 1. This loading dose should produce a concentration of 9.3 ng/ml in the first month. The next two dosages should be 250 mg IM q 28 d, which would produce a steady-state concentration of 9.4 ng/ml. This dosing nomogram is only a guideline or a starting point. The patient must be continuously monitored for therapeutic response and adverse effects (Perry and Alexander 1991).
Stable patients on antipsychotic maintenance therapy can be successfully maintained on relatively low doses of haloperidol decanoate. In stable chronic schizophrenic patients, it has been suggested that the maintenance dose be tapered at a rate of 20% every 6 months. Nyberg et al (1995) documented the validity of this recommendation. Eight stable chronic schizophrenic outpatients who were stable on a haloperidol decanoate dose of 30-50 mg/4 weeks for the last 5-15 months were studied. D2 receptor occupancies and haloperidol concentrations were measured at week 1 and week 4 following their depot antipsychotic injection. The mean D2 receptor occupancy at week 1 was 73% (range = 60-82%) and week 4 was 52% (20-74%) while the corresponding haloperidol concentrations were 4.6 ng/ml (2.9-9.7 ng/ml) and 2.3 ng/ml (1.0-4.4 ng/ml). Despite the low D2 receptor occupancies and haloperidol concentrations relapse was prevented in these patients. Thus continuous tapering of the depot antipsychotics is possible for many chronic schizophrenic patients.
Tugg et al (1997) studied the hypothesis that the severity of negative symptoms may be correlated with the amount of medication received. This hypothesis was studied in 31 outpatient schizophrenic and schizoaffective disorder patients who had been on a stable dose of antipsychotic medication for at least 3 months. Raters completing the symptom and side effect ratings were not blind to antipsychotic dose. Negative symptoms were not correlated with either antipsychotic dose or plasma levels. Positive symptoms were, however, significantly correlated with both dose and plasma levels. Total AIMS scores were significantly correlated with both dose and plasma levels. Only dose contributed significantly to the AIMS score (p<0.05). Neither dose nor plasma levels were significantly correlated with either akathisia or parkinsoniam side effects.
THERAPEUTIC DRUG MONITORING
The clinical value of employing antipsychotic plasma concentrations as a monitor for dosing schizophrenic patients is a widely debated and complicated issue. Numerous reviews with varying opinions have been written over the years. At present, antipsychotics differ from tricyclic antidepressants in that plasma concentration measurements are not routinely used by most clinicians as a tool to optimize dosing. This is primarily due to a lack of well-designed research supporting the utility of antipsychotic blood concentrations. Also, most laboratories do not routinely perform antipsychotic assays. Routine plasma level monitoring of the antipsychotics has clinical utility for several reasons. Interindividual pharmacokinetic variation usually makes it unrealistic to dose patients on a by weight basis. Excessively high concentrations may be associated with clinical deterioration of the patient because of increased adverse effects and antipsychotic toxicity. Additionally, plasma level monitoring assures compliance. Perry and Smith (1993a) reviewed the antipsychotic blood level clinical studies with technically appropriate design and methodology. Additionally, an internal analysis was conducted for those studies that supplied sufficient raw data. To determine if a relationship existed between the plasma concentration of the antipsychotic and therapeutic response, receiver operating characteristic (ROC) curves were generated and the sensitivity and specificity of the blood level data was assessed utilizing chi-square analyses. Perry et al (1991) demonstrated the utility of this analytical methodology in evaluating their clozapine data.
For a study to be considered for review and further analysis, several minimum criteria had to be met. First, to establish a reasonably homogeneous diagnostic set of patients, a diagnosis suggesting schizophrenia was required. It has been their experience in analyzing antipsychotic blood level data with mixed diagnostic patient populations (e.g., schizophrenic, schizophreniform, and schizoaffective) that the results of an analysis can change considerably when only schizophrenic patients are considered alone without inclusion of all psychotically ill patients. Thus, the preferred diagnostic criteria for schizophrenia included Research Diagnostic Criteria (RDC) (Spitzer et al 1978), DSM-III (American Psychiatric Association 1980), or the DSM-III-R (American Psychiatric Association 1987). Exceptions to this rule were made for some of the older studies that were performed before use of these criteria was widespread. Furthermore, only studies that were treating acutely ill patients were considered. Next, the study was required to utilize a fixed dose of antipsychotic for a minimum of 2 weeks. Studies that allow upward dose titration during the observation period always bias the results toward a curvilinear relationship. A validated psychosis rating scale such as the Brief Psychiatric Rating Scale (BPRS) or the New Haven Schizophrenic Index (NHSI) was essential to quantify psychopathology. Acceptable antipsychotic assay methodology included highly specific assays such as high performance liquid chromatography (HPLC), gas-liquid (GLC) chromatography, and some radiolabeled immunoassays (RIA). The radio-receptor assay (RRA) was not acceptable. The RRA measures the total dopamine receptor-blocking activity in the blood and therefore accounts for not only parent drug but active metabolites as well. Antipsychotic blood to brain distribution ratios because of differences in protein binding in the plasma and the CSF may differ between antipsychotics. Since only free and unbound drug is active in the brain, the plasma RRA may not adequately mirror the amount of active free drug in the CNS. It was not surprising that a review of these studies concluded that the RRA assay was not a useful tool for plasma concentration monitoring of antipsychotics (Dahl 1986). Thus, studies using the RRA were excluded from this review.
For their internal analysis, the optimal split or cut point for the antipsychotic concentrations was estimated by drawing receiver operating characteristic curves (ROC) (Mossman and Somoza 1991). ROC curves are ideal for this purpose since they provide an objective technique to identify key antipsychotic concentrations in relation to response. The optimal split for the drug concentrations was estimated ROC. The ROCs were constructed to graph each data point separately. A 30% reduction in psychopathology was used as an a priori criterion of response unless another measure was specified by the authors of the studies reviewed.
Tables 5 and 6 present the recommended therapeutic ranges for each study along with the sensitivity and specificity values for these data. Of the drugs reviewed, haloperidol, trifluoperazine, thiothixene, clozapine and olanzapine have been the subjects of well-designed studies that document reasonably consistent relationships between blood concentrations and therapeutic response. Of these the case for the clinical use of plasma concentrations of haloperidol is by far the strongest. Inspection of Table 5 indicates that there are four studies that suggest a lower limit of 5-9.5 ng/ml and two studies that define 14-15 ng/ml as the upper therapeutic limit. A meta-analysis on the 7 haloperidol studies concluded that the therapeutic range was 5-18 ng/ml (Perry and Smith 1993a). One subsequently published haloperidol study reported a similar therapeutic window of 5-17 ng/ml (Ulrich et al 1998). Patients who fail a six-week trial of haloperidol within this therapeutic range ought to be considered for an alternative agent. There are only single studies for thiothixene, trifluoperazine, and clozapine that document a correlation between therapeutic response and blood level. Based on sample size considerations and these analyses it seems logical that next drug of choice would be trifluperazine. The ROCs analysis makes a strong case for a therapeutic range of 1.05-2.25 ng/ml. Thus trifluperazine would be an appropriate second line antipsychotic if the patient is not considered treatment refractory. However, if treatment refractory, risperidone and then clozapine would be the logical treatments remaining for the patient.
Clozapine. A clozapine concentration of > 504 ng/ml is considered therapeutic (Perry and Miller 1993b). This recommended plasma concentration threshold differs from their original recommendation of > 350 ng/ml (Perry et al 1991). This is because the original recommendation was based on the non-schizophrenic specific rating scale of the BPRS. The second recommendation of > 500 ng/ml is based on the Scale for the assessment of Positive Symptoms (SAPS) and Scale for the assessment of Negative Symptoms (SANS). The Brief Psychiatric Rating Scale (BPRS) suggests a lower limit of 397 ng/ml as shown in Table 5. However, the SAPS/SANS recommendation produces somewhat better sensitivity than the BPRS. These two validated scales were designed to specifically assess the positive and negative symptoms of schizophrenia (Andreasen 1982, Andreasen 1983). The clozapine dosing recommendation has been replicated by three other studies. A comparison of these three studies and the Perry et al data are presented in Table 6.
It has been suggested that clozapine's active metabolite, desmethylclozapine is a biological marker for impending clozapine-induced granulocytopenia and agranulocytosis (Gerson et al 1994). Combs and Perry (1997) conducted a retrospective chart review of 58 schizophrenic patients who received a course of clozapine therapy. However, no significant correlations were found between the granulocyte counts and the patient demographic variables of clozapine and desmethylclozapine plasma concentrations, clozapine/norclozapine ratio, age, gender, clozapine dose, smoking status, and race. To the contrary, desmethylclozapine plasma concentrations correlated positively with granulocyte counts. Thus desmethylclozapine is not a clinically useful marker for monitoring the effect of clozapine on granulocyte integrity.
Risperidone. No studies have been successful at identifying a therapeutic range for risperidone plasma concentrations. It is recommended to keep risperidone doses < 6 mg/day to minimize the risk of EPS (Chouinard et al 1993). Newer clinical based studies have suggested that lower doses of risperidone (3-4 mg/day) may be effective in acute schizophrenia (Love et al 1999, Lane et al 2000). A weak relationship between risperidone and the daily risperidone dose (mg/d) has been reported although, a more robust relationship between total risperidone plasma concentration (risperidone + 9-hydroxy risperidone) and dose (r2=0.50, n=280) was observed (Aravagiri et al 1998). This finding suggested that studies pursuing blood level to response relationships for risperidone ought to correlate the total active drug concentration with the rating scale change scores. One study using this strategy was unable to discern a significant correlation between the total risperidone concentration or daily risperidone dose and an adverse effect scale (Olesen et al 1998). An additional point of clinical interest was that of the 22 patients administered the clinically optimum dose of 6mg/d, 90% of the patients had total risperidone concentrations between 50-150 nmol/L (21-62 ng/ml). Lane et al (2000) titrated 30 acutely ill schizophrenic inpatients to either risperidone < 6 mg/d or 6 mg/d for 6 weeks. The dose remained constant from days 3-42. Of note, in the low- and high-dose groups, steady-state plasma risperidone (7.8 vs 7.3 ng/ml), 9-hydroxy-risperidone (32.6 vs 42.4 ng/ml), and risperidone plus 9-hydroxy-risperidone (40.4 vs 49.7 ng/ml) were similar at endpoint. No significant linear or curvilinear correlations were observed between any of these plasma parameters and change scores on the total PANSS, positive symptom PANSS, and negative symptom PANSS.
Olanzapine. Following a 2-9 day placebo lead-in, 79 inpatients with DSM-III-R schizophrenia were placed on a olanzapine dose of 10 mg/d or 1 mg/d for up to six weeks with blood samples (24 hour post-dose) being obtained weekly during this period (Beasley et al 1996a). Receiver operating characteristic curve analyses of Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Symptoms Scale (PANSS) data suggested a therapeutic threshold of 9.3 ng/ml. Based on a > 20% decrease in BPRS scores, 45% of patients with olanzapine plasma concentrations > 9.3 ng/ml responded. However, only 14% of patients with concentrations below this level responded (Perry et al 1997). The sensitivity and specificity of this threshold plasma concentration were 60% and 81%, respectively. These parameters indicate that dosing olanzapine based on blood levels may optimize response in acute schizophrenics.
A second therapeutic drug monitoring study with olanzapine has been conducted using 12-hour post-dose olanzapine levels (Perry et al 2001). Acutely ill schizophrenic patients received between 2.5 - 17.5 mg/day as part of the North American Olanzapine Trial (Beasley et al 1996b). Using the definition of response established by Kane et al (1988), an olanzapine concentration > 23.2 ng/ml was a significant predictor of clinical response. The response rate above this threshold was 52% compared with 25% below 23.2 ng/ml.
A clinically significant drug interaction has been reported between olanzapine and carbamazepine, a known hepatic enzyme inducer. Coadministration has been reported to increase olanzapine clearance by as much as 50% and decrease olanzapine concentrations by 36% (Lucas et al 1998, Olesen and Linnet 1999). As is the case with clozapine, it is preferable to avoid using carbamazepine in patients requiring an antiepileptic agent.
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Table 5. Receiver operating characteristic curve analyses to determine therapeutic range for neuroleptic drugs. |
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Study and drug |
(ng/ml) |
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p |
(ng/ml) |
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p |
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Magliozzi et al 1981 haloperidol |
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0.01 |
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Garver et al, 1984 haloperidol |
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0.005 |
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Linkowski et al 1984 haloperidol |
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Santos et al 1989 haloperidol |
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Kelly et al 1990 haloperidol |
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0.03 |
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Bigelow et al 1985 haloperidol |
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Van Putten et al 1985 haloperidol |
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Meta-analysis haloperidol therapeutic window |
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Janicak et al 1989 trifluoperazine |
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< 0.005 |
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NS |
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therapeutic window |
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Mavroidis et al 1984a thiothixene |
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NS |
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NS |
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therapeutic window |
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Mavroidis et al 1984b fluphenazine |
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NS |
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Perry et al 1991 clozapine |
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Table 6. Clozapine TDM studies recommending a therapeutic threshold concentration above 350 ng/ml. |
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Perry et al 1991 |
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Perry et al 1992 (revised) |
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Hasegawa et al 1993 |
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Potkin et al 1994 |
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Kronig et al 1995 |
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Spina et al 2000 |
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PROSPECTIVE HALOPERIDOL DOSING
By Half-Life. Miller et al (1990b) designed a prospective dosing protocol for haloperidol. The method requires the administration of a 20 mg test dose of haloperidol to each subject. Blood samples (10 cc) were drawn at 12 hr and 24 hr. The plasma levels obtained were analyzed to determine the elimination rate constant and half-life. From these data R, and the daily accumulation factor, was computed. The kinetic data produced were then applied to development of various dosing schedules based on predictions of CSSmin TD in each individual patient. The accumulation factor R was calculated by equation 1 below,
where Ke is the elimination rate (h-1) and T = dosing interval (h). The steady state tricyclic level for a specific dose of drug is calculated:
where CSSmin is the minimum serum haloperidol level at steady state (ng/ml), D is the dose administered (mg), TD is the test dose (mg), and CSSmin TD, the minimum serum concentration produced by the test dose.
A total of 27 patients were dosed according to the method. The correlation coefficient (r) of the observed haloperidol plasma levels to the predicted haloperidol levels for these patients was 0.86 (p < 0.001).
The computer software (Apple or IBM) for running this prospective dosing methods is available from Dr. Perry on request.
By Weight. Previous data suggest the possibility that haloperidol daily dosing requirements may be confounded by smoking and at higher doses capacity limited metabolism. Perry et al (1998) studied 40 hospitalized patients suffering from acute exacerbations of schizophrenia were treated for two weeks with fixed oral doses of haloperidol ranging from 10-70 mg/d (0.13-0.95 mg/kg/d) that produced mean steady-state concentrations between 4.5-55.4 ng/ml. An analysis using MANOVA found no significant differences between the smoking and nonsmoking groups were obvious for the factors of weight, age, sex, daily doses, steady-state clearance, and steady-state haloperidol plasma concentrations at week-1, week-2 and their mean. However, multiple linear regression analysis showed a significant interaction between the variables of smoking and dose when the data was curve fitted as a log-log function. The haloperidol plasma concentration to dose relationship was best described by the following two equations: for nonsmokers,
haloperidol (ng/ml) = e[ 0.467 * ln(dose) + 3.397]
and for smokers,
haloperidol (ng/ml) = e[1.088 * ln(dose) + 3.716].
If prospective dosing according to the Miller (1990) method is not a viable approach to dosing patients, figure 1 can be utilized to dose haloperidol patients according to their weight.
Figure 1. Haloperidol plasma concentration to dose relationship using linear scaling, where for nonsmokers [HLP] (ng/ml) = e[ 0.467 * ln(dose) + 3.397] and for smokers [HLP](ng/ml) = e[1.088 * ln(dose) + 3.716].
PROSPECTIVE CLOZAPINE DOSING
Previous work has suggested factors such as gender, smoking behavior, dose and age affect the amount of drug a patient requires to achieve a desired plasma concentration of clozapine. Plasma clozapine concentrations ranging from 350 to 500 ng/mL have a greater likelihood of response. Without the aid of clozapine plasma concentration monitoring, 3 to 6 months are recommended for a therapeutic trial of clozapine. Data suggest that the time to response can be reduced by administering a dose that produces a therapeutic clozapine concentration. To predict an estimated dose that would give patients a desired therapeutic clozapine plasma concentration, a cohort of 77 patients was collected via retrospective chart review and/or patient interview. Clozapine plasma concentrations and demographic variables were obtained. Multiple-linear regression was utilized to examine the relationship between the steady-state plasma clozapine concentration and the independent variables. The independent variables that significantly correlated with the clozapine concentration were dose (mg/day), smoking (yes/no), gender, and a dose-gender interaction variable. The model explains 40% of the variance of the clozapine concentrations (F=11.95, p<0.0001, r2=0.40). Two equations, one for males, i.e., (clozapine (ng/mL) = 227 + 120 (smoke) + 0.265 (dose)) and one for females, i.e., (clozapine (ng/mL) = 120 (smoke) + 1.615 (dose) - 171) were derived to predict clozapine steady-state plasma concentrations to serve as guide to clinicians (Perry et al 1998). Figure 2 presents a clozapine dosing nomogram that illustrates the relationship between dose and clozapine plasma concentration for smoking and nonsmoking females and males.
DRUG HOLIDAYS
The decision of discontinuing antipsychotic treatment because of the risk or appearance of tardive dyskinesia is a continual problem with which clinicians must contend. Drug holidays have been recommended by some investigators as a means for lowering this risk. It is assumed that a periodic discontinuation of medication would reduce the overall risk of tardive dyskinesia by reducing total drug intake.
However, both animal and human studies have indicated that intermittent drug therapy may actually increase the risk of tardive dyskinesia. Weiss and Santelli (1978) found that monkeys in which dyskinesia did not develop with continuous administration of haloperidol became dyskinetic when switched to intermittent treatment. Two studies (Jeste et al 1979a, Bannet et al 1980) with the supersensitivity model in rodents concluded that interrupted administration of an antipsychotic did not prevent or reduce development of dopaminergic supersensitivity. Two reports (Degivity 1969 and Jeste et al 1979b) suggested patients receiving interrupted antipsychotic treatment were more likely to have persistent dyskinesia than patients who had almost continuous drug treatment. McCreadie et al (1980) reported a higher incidence of tardive dyskinesia in patients receiving intermittent pimozide than in those being treated regularly with fluphenazine decanoate.
These findings may support the observation of the high incidence of tardive dyskinesia among certain patients with affective illness (Simpson 1980). These patients tend to receive intermittent antipsychotic treatment. There is little clinical or experimental evidence to support the notion that drug interruptions lower the incidence of persistent tardive dyskinesia. Patients who require continuous antipsychotic treatment should receive the lowest dose possible to control their psychotic symptoms.
Figure 2. Association of plasma clozapine concentration to clozapine dose.
|
Table 7. Pharmacokinetics of typical antipsychotics (Goodman and Gilman 1996, Perry et al 1997, Baselt 2000). |
|||||
|
Drug |
Oral Biovailabilty (%) |
Plasma Protein Binding (%) |
Clearance (ml/min/kg) |
Volume of Distribution (L/kg) |
t 1/2 (h) |
|
chlorpromazine |
32 ± 19 |
95-98 |
8.6 ± 2.9 |
21 ± 9 |
30 ± 7 |
|
fluphenazine decanoate |
n/a |
99 |
-- |
220 |
5-12 days |
|
fluphenazine enanthate |
n/a |
99 |
-- |
220 |
3-4 days |
|
fluphenazine HCl |
< 50 |
99 |
-- |
220 |
13-58 |
|
haloperidol decanoate |
n/a |
-- |
-- |
-- |
21 days |
|
haloperidol HCl and lactate |
60 ± 18 |
92 ± 2 |
11.8 ± 2.9 |
18 ± 7 |
18 ± 5 |
|
loxapine |
-- |
-- |
-- |
-- |
6-8 |
|
molindone |
-- |
-- |
-- |
-- |
1.5 -6 |
|
perphenazine |
60-80 |
-- |
-- |
10-36 |
10-20 |
|
thioridazine |
10-60 |
96 |
18 |
10 |
10-30 |
|
thiothixene |
-- |
-- |
-- |
-- |
12-36 |
|
trifluoperazine |
-- |
> 90 |
-- |
10-35 |
7-18 |
|
Table 8. Pharmacokinetics of atypical antipsychotics (Goodman and Gilman 1996, Perry et al 1997, Baselt 2000, Goren and Levin 1998). |
|||||
|
Drug |
Oral Biovailabilty (%) |
Plasma Protein Binding (%) |
Clearance (ml/min/kg) |
Volume of Distribution (L/kg) |
t 1/2 (h) |
|
clozapine |
55 ± 12 |
> 95 |
6.1 ± 1.6 |
5.4 ± 3.5 |
12 ± 4 |
|
risperidone |
66 ± 28 |
89 |
5.4 ± 1.4 |
1.1 ± 0.2 |
3.2 ± 0.8 |
|
olanzapine |
-- |
93 |
-- |
10-20 |
21-54 |
|
quetiapine |
~ 9 |
83 |
-- |
10 |
2.7-9.3 |
|
ziprasidone |
-- |
> 99 |
7.5 |
1.5 |
6.6 |
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