Pharmacologic and Pharmacokinetic Considerations in Choosing an Antipsychotic

Larry Ereshefsky

Larry Ereshefsky, Pharm.D., F.C.C.P., B.C.C.P.

© CopyrightRecent advances in 2000our understanding Physicians of schizophrenia Postgraduatealong with neuroscience insights Press, into anti- Inc. psychotic medication mechanisms of action have led to a renaissance in new drug development, including an expanded therapeutic spectrum encompassing more of the symptoms encountered in schizophrenia. Atypical antipsychotics, or new generation therapies, also demonstrate greater selec- tivity for therapeutic actions than for extrapyramidal symptoms (EPS). Our modern armamentarium of drugs spans a wide range of pharmacologies, and it is more accurate to envision shades of gray rather than a black-and-white description for typical versus atypical properties of medications. As our paradigms for antipsychotic efficacy have shifted, a reexploration of the “older” neuroleptics is warranted to determine if they possess pharmacologic attributes that might have been overlooked during the era of high-dose neuroleptic therapy. Loxapine appears to be in the center of this spectrum, somewhere between haloperidol and risperidone. Dosing implications for drugs with a more even seroto-

nin-2A (5-HT2A) receptor and dopamine-2 (D2) receptor blocking effect are discussed. Loxapine might have a window of partial atypicality at doses ≤ 50 mg/day. These lower doses might have potential as both monotherapyOne in personal responsive patientscopy maywith persistent be printed psychotic disorders and as an adjunctive treatment in partially responding patients on concurrent atypical antipsychotic treatments. The pharmacologic properties of loxapine within its usable dosage range are quite complex and are the net sum of the parent’s plus metabolites’ contributions (demethylation and hydroxylation by cytochrome P450 enzymes). These pharmacologic effects include α-adrenergic blockade, inhibition of the noradrenergic transporter protein (reuptake inhibition), and antimuscarinic effects. Drug interactions and cigarette smoking might alter the parent-to-metabolite concentration ratios, affecting the relative atypicality of this antipsychotic therapy. Moreover, with the intramuscular formulation, which does not undergo first-pass metabolism, the parent compound of loxapine, i.e., not its metabolites, is predominantly detected in the plasma of patients, reducing the likelihood for EPS during emergency in- terventions in patients with positive symptoms. Further study is warranted to determine loxapine’s place in our treatment of schizophrenia. (J Clin Psychiatry 1999;60[suppl 10]:20–30)

he serendipitous discovery of neuroleptic medica- amphetamine and if they caused catalepsy, a form of extra- T tions (from the French neuroleptique, meaning “to pyramidal disturbance.1Ð3 Compounds that did not cause clasp the neuron”) revolutionized our treatments for per- catalepsy in animal models were not considered to be ef- sistent psychotic disorders. The observation that these fective antipsychotic agents, e.g., clozapine.4 The theory agents almost invariably induced parkinsonian features of the primary role of dopamine in mediating psychosis led to simple animal models to screen these putative medi- was supported by the pharmacologic and neurochemical cations. In rodent models, drugs were determined to be characterization of the effects of stimulants on behavior, antipsychotics if they antagonized the excitatory effects of Parkinson’s disease and its treatment, and neuroleptic activities in both human and animal models. Although

dopamine-2 (D2) receptor blockade is still a component of the pharmacologic profiles of all marketed antipsychotic From the College of Pharmacy, The University of Texas at agents, the modulation of other biogenic amines, indirect Austin, the Departments of Pharmacology and Psychiatry, The University of Texas Health Science Center at San Antonio, and effects on excitatory amino acids, and possibly peptidergic the Clinical Research Unit, San Antonio State Hospital. systems play a role in many new generation, or atypical, Supported in part by an educational grant from Watson 5Ð7 Laboratories, Inc. antipsychotic therapies. Clozapine’s complex pharma- Presented at the closed symposium “What Makes an cologic profile is illustrated in Figure 1. Neuroscience in- Antipsychotic Atypical?” which was held in Dallas, Tex., May sights into brain function and the development of many 6–7, 1998, and was supported by an unrestricted educational grant from Watson Laboratories, Inc. novel antipsychotics with a wide array of pharmacologic Reprint requests to: Larry Ereshefsky, Pharm.D., F.C.C.P., effects have led to a dramatic paradigm shift in our B.C.C.P., Pharmacotherapy Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., conceptualization of schizophrenia and other psychotic San Antonio TX 78284-6220 (e-mail: [email protected]). disorders.8Ð10

20 J Clin Psychiatry 1999;60 (suppl 10) Pharmacologic and Pharmacokinetic Considerations

Figure 1. Summary of Neurochemical Activities for Figure 3. Use Pattern of Atypical Antipsychotics in 2 Acute Clozapinea Care Units: Evaluation of Adjunctive Polytherapya

Indirect NMDA 80 α Neurotensin, Acute care unit 1 1 substance P/substance K 70 Acute care unit 2 5-HT6 60 5-HT H 1 50 2A NE transporter 40 5-HT Clozapine inhibitor 3 30 % of Patients © Copyright 2000 Physicians 20Postgraduate Press, Inc. 2C 5-HT 10 D4 M D 1 D 1 0 2 Olanzapine Olanzapine Olanzapine Quetiapine Risperidone > 5 and ≤ 15 > 15 mg/d + Haloperidolb ≈ 440 mg/d + ≈ 5 mg/d + mg/d HaloperidolbbHaloperidol a α α Abbreviations: 1 = 1-adrenergic receptor blockade, aL.E., unpublished data, September 1998. N = 70 for olanzapine, 5-HT = serotonin receptor blockade (subtypes 2A, 2C, 3, and 6), N = 30 for quetiapine, N = 60 for risperidone. Acute care unit 1 D = dopamine receptor blockade (subtypes 1, 2, and 4), predominantly utilized lower doses of olanzapine as demonstrated by H1 = histamine-1 receptor blockade, M1 = acetylcholine muscarinic-1 proportion of patients taking a mean of 12 mg/day, and used adjunctive receptor blockade, NE = norepinephrine, NMDA = glutamate haloperidol in 19% of patients. Acute care unit 2 predominantly N-methyl-D-aspartate receptor. utilized higher doses of olanzapine, averaging approximately 19 mg/day in 78% of patients. Adjunctive haloperidol use was employed in 4% of patients. Quetiapine plus haloperidol adjunctive therapy was One personal copy mayused bein approximately printed 30% of patients, while risperidone-treated Figure 2. Summary of Neurochemical Activities for Loxapine patients used adjunctive haloperidol in less than 6% of cases. and Its Metabolites bPercentages shown are percentages of patients receiving the atypical agent who also received haloperidol. α 1

5-HT sus response issues and the role of loxapine in the treat- H1 2A ment of schizophrenia and other psychotic disorders. Pro- NE transporter Loxapine + inhibitor spective randomized clinical trials are needed to validate Metabolites many of these suggestions. 5-HT transporter 2C inhibitor WHAT IS THE PLACE OF OLDER TREATMENTS IN 5-HT D4 THE MANAGEMENT OF SCHIZOPHRENIA? M1 D1 D2 More than 50% of patients with acute psychiatric disorders admitted at San Antonio State Hospital received atypical therapy, reflective of the national trend, because As our paradigms for antipsychotic efficacy have of the perceived advantages for the newer atypical anti- shifted, a reexploration of the “older” neuroleptics is war- psychotics, e.g., superiority for relieving negative symp- ranted, to determine if they possess pharmacologic at- toms and their effectiveness in improving several domains tributes that might have been overlooked during the era of of cognitive and social function.19Ð24 However, rapid calm- high-dose neuroleptic therapy. As discussed in Stahl’s11 ing of agitated or aggressive patients is not always evident and in Richelson’s articles12 in this supplement, loxapine’s in many of our patients with orally administered atypical pharmacologic profile includes clinically significant medications. There is a continuing need for intramuscular serotonin-2A (5-HT2A) antagonism along with D2 block- therapy using benzodiazepines, e.g., lorazepam, neurolep- ade. Additionally, loxapine’s metabolism is complex, lead- tics, or combinations of both, during the crisis manage- ing to the production of several compounds with psycho- ment phase for patients with psychotic disorders.25Ð27 The tropic action.13Ð15 Pharmacologic effects for loxapine and need for coadministered typical neuroleptics in patients its metabolites also include biogenic amine transporter in- started on atypical medications is surprisingly frequent; α hibitor activity, and -adrenergic blocking effects, as illus- the need is lowest with risperidone (the most potent D2 re- trated in Figure 2.8Ð10,16Ð18 At the highest doses used, anti- ceptor antagonist among the atypical medications) and muscarinic effects also become a significant factor. This highest with quetiapine (the least potent D2 antagonist), as article reviews pharmacokinetic and pharmacodynamic illustrated in Figure 3 (L.E., unpublished data, September considerations relevant to the use of loxapine and presents 1998). A retrospective 6-month analysis of the pharmacy the implications of these findings with regard to dose ver- computer data for 2 acute admitting units was performed,

J Clin Psychiatry 1999;60 (suppl 10) 21 Larry Ereshefsky unit 1 employing moderate-dose olanzapine and unit 2 oral concentrate or intramuscular formulation in patients employing high-dose therapy. Concomitant haloperidol admitted with acute illness started on atypical therapy, use for these 2 units differed, despite no differences in pa- might be preferred to the more traditional use of haloperi- tient demographics, psychiatric severity, or length of stay. dol. These possible roles for loxapine are further discussed Quetiapine and risperidone usage was similar on both below. units, and as displayed in Figure 3, concomitant haloperidol usage was greatest with quetiapine and least with ris- IS LOXAPINE SUPERIOR TO peridone. OTHER ANTIPSYCHOTICS? However, the atypical medications, if administered on a subchronic basis, demonstrate equivalent or superior ef- The literature weakly suggests that loxapine can im- ficacy in reducing© Copyright aggressive behavior 2000 and positive Physicians symp- prove Postgraduate some symptoms in schizophrenia Press, significantly Inc. better toms.28Ð30 The use of adjunctive therapies should therefore than standard neuroleptic treatment. For instance, Bishop be reserved for those patients requiring rapid reductions in and colleagues36 demonstrated, in a meta-analysis of 11 these symptoms or in those in whom there is only partial double-blind controlled trials, that patients with paranoia response despite optimization of the atypical dosage. demonstrated significantly more improvement on loxapine Moreover, despite the popularity of benzodiazepines as (range, 20Ð120 mg/day) than on trifluoperazine (range, adjunctive calming agents, they are detrimental to cogni- 20Ð60 mg/day) or chlorpromazine (range, 100Ð1200 tive and memory processes.31,32 High-potency antipsy- mg/day) over 12 weeks of treatment. Additionally, a trial chotic agents, when used in the acute setting, are also by Paprocki and colleagues37 demonstrated superior ef- likely to incur extrapyramidal symptoms (EPS), hence the fects for paranoia compared with haloperidol. Reinforcing routine use of prophylactic anticholinergic antiparkinsoni- the potential of lower doses of loxapine in the treatment of an therapies. These antimuscarinic agentsOne personal also are detri- copy maypatients be printedwith schizophrenia and schizoaffective disorder is mental for cognitive function.33 Therefore, management a study by Moyano38 that used an average maximum dose of aggression with an antipsychotic that is less likely to of 20Ð80 mg/day in a 12-week comparison with trifluoper- incur EPS is highly desirable. azine at an average maximum dose of 20Ð40 mg/day. Lox- In the extended care units at San Antonio State Hos- apine was significantly better for reductions in emotional pital, > 80% of patients with persistent psychotic disor- withdrawal and blunted affect and demonstrated a possible ders are receiving atypical antipsychotics (D. Dugan, trend for advantage on the anergia subscale of the Brief Pharm.D., Clinical Research Unit, San Antonio State Hos- Psychiatric Rating Scale (BPRS) at week 12 (significantly pital, written communication, October 1998). Interest- better at week 8 than trifluoperazine). ingly, despite past histories of treatment refractoriness to In another study, loxapine at doses up to 100 mg/day typical antipsychotics, more than 50% of these patients was compared with chlorpromazine at doses of up to 1000 are receiving a second (and in some cases a third) antipsy- mg/day in a 12-week trial.39 Although both drugs were chotic agent. The most frequently co-prescribed medica- equally effective based on total BPRS score change, ad- tions with clozapine are haloperidol or risperidone, both vantages for loxapine were reported in the following areas potent D2 receptor blockers. It appears that for patients based on mean improvement from baseline: Clinical Glo- with persistent and treatment-resistant psychotic features, bal Impressions-Severity of Illness scale (CGI-S), BPRS and for those with aggressive behavior patterns, D2 recep- emotional withdrawal scale item, the total Nurses’ Obser- tor blockade is a necessary component of the total phar- vation Scale for Inpatient Evaluation (NOSIE) score, and macologic treatment. several individual NOSIE items (social competence, social The pharmacologic and drug metabolism characteris- interest, irritability, and manifest psychosis). Superiority tics of loxapine (plus its metabolites) are surprisingly rich, over chlorpromazine for the following side effects was with many of these effects potentially useful in the treat- also reported: sedation, dizziness, orthostatic hypotension, ment of schizophrenia. As demonstrated in articles by and antimuscarinic effects. However, there were no differ- Kapur and colleagues34 and by Richelson,12 loxapine dem- ences in EPS between loxapine and chlorpromazine in this onstrates potent D2, D4, and 5-HT2A blockade. It is sug- study. gested that at low doses, 5-HT2A blockade will counterbal- Parenteral loxapine succinate was a useful treatment in ance D2 blockade, resulting in a drug with a partially 6 very disturbed psychotic patients, even when previous atypical profile that includes a propensity to cause EPS ly- treatments had failed.40 Similarly, Ereshefsky and col- ing somewhere between that of haloperidol and that of leagues41 reported that in an open trial, 3 treatment- risperidone.35 At intermediate doses, loxapine is a well- resistant patients with chronic illness who were previously tolerated neuroleptic, while at high doses, it is a pharma- unresponsive to 3Ð7 prior neuroleptic therapies demon- cologically rich drug with multiple receptor effects, and strated dramatic improvement, especially in paranoid and might work in treatment-refractory patients (see Figure 2). aggressive symptoms, with very high dose loxapine, e.g., Additionally, the adjunctive use of loxapine, as either the 250 to 400 mg/day. These 3 cases represent the use of lox-

22 J Clin Psychiatry 1999;60 (suppl 10) Pharmacologic and Pharmacokinetic Considerations

augmentation for stable, poorly respon- Table 1. Affinity of Antipsychotics for Human (in vitro) Receptorsa × Ð7 sive patients on clozapine therapy demon- Ratio of 1/Kd 10 for × Ð7 × Ð7 × Ð7 α 1/Kd 10 1/Kd 10 (Ðlog Kd 5-HT2A)/ 1/Kd 10 1-Adrenergic strated a more than 20% average im- 43 Drug/Metabolite for D2 for 5-HT2A (Ðlog Kd D2) for M1 Receptor provement from baseline. The only Haloperidol 39 1.6 0.84 0.0042 5.9 double-blind, placebo-controlled, add-on Fluphenazine 125 5.3 0.85 0.053 11 study in the literature used sulpiride addi- Clozapine 0.47 39 1.29 11 15 Risperidone 27 660 1.17 0.0029 37 tion to clozapine. Significant incremental Loxapine 6.1 73 1.14 0.22 3.6 improvement from baseline was again ob- Amoxapine 5.6 97 1.16 ND ND served in that study by means of standard- 7-Hydroxyloxapine 108 359 1.06 ND ND 44 7-Hydroxyamoxapine 93 238 1.05 ND ND ized psychiatric rating scales. Pharmaco- 8-Hydroxyloxapine© Copyright 2.6 14 2000 1.07 Physicians ND NDPostgraduatekinetic drug interactions Press, did Inc. not appear to 8-Hydroxyamoxapine 1.5 14 1.13 ND ND play a significant role in these reports and aData from reference 12. Abbreviations: D = dopamine-2, 5-HT = serotonin-2A, 2 2A do not explain the additive effects of com- Kd = equilibrium dissociation constant in molarity, M1 = muscarinic-1, ND = not done. bined therapies. Interestingly, loxapine and risperidone are remarkably similar in 12 Figure 4. Metabolism of Loxapine Via Cytochrome P450 their 5-HT2A/D2 receptor affinity ratios (Table 1). Well- (CYP) Enzymesa controlled fixed-dose loxapine studies are needed to vali- Loxapine date loxapine’s potential superiority over other medica- Demethylation Hydroxylation CYP1A2 (?) CYP2D6 (?) tions and to document its usefulness as an adjunctive CYP3A4 (?) therapy in partially responsive patients. Amoxapine One7-Hydroxyloxapine personal copy may be printed and PHARMACOKINETIC VERSUS 8-Hydroxyloxapineb Hydroxylation PHARMACODYNAMIC CONSIDERATIONS CYP2D6 (?) CYP3A4 (?) To understand the time course for clinical effect and to 7-Hydroxyamoxapine appreciate the interrelationship of dosage with the phar- and macologic properties of an antipsychotic requires the 8-Hydroxyamoxapineb integration of pharmacokinetic and pharmacodynamic aData from references 11, 12, and 14Ð18. bHydroxylation results in 2 metabolites. considerations. Loxapine, a tricyclic, dibenzoxazepine antipsychotic, is metabolized to several active compounds. Figure 4 illustrates loxapine’s complex drug metabolism to apine in an extended care forensic population rather than psychoactive products.11,12,14Ð18 Research has demonstrated in the more general acutely ill psychiatric patient popula- that many antipsychotics designated as atypical possess tion typically enrolled in efficacy and safety studies. Ex- significant D2 receptor blockade but, more importantly, trapyramidal symptoms were not experienced by these also has demonstrated a more potent pharmacologic effect high-dose patients, but mild anticholinergic effects includ- associated with atypicality.1,45,46 The less the difference in ing numbness did occur. affinity values between D2 and other significant pharma- A recent case series demonstrated a substantial benefi- cologic modifying effects, the more important dosage will cial effect (7 of 7 patients) from the addition of loxapine to become in preserving the atypicality of the antipsychotic clozapine-resistant patients previously optimized for the agent.11 Of considerable interest with risperidone is the ap- dose of the atypical agent (2 of 7 patients demonstrated a parent dose-related shift from atypical to more typical an- dramatic response on the basis of BPRS evaluations).42 tipsychotic as the dosage is increased. In contrast, cloza- The loxapine doses ranged from 25 to 200 mg/day, al- pine over its entire dosage range does not produce EPS. though no attempt at identifying minimum effective dose Loxapine’s ratio of the equilibrium dissociation constants or controlling for time effects was made. These cases are in molarity Kd for 5-HT2A/D2 along with those of represen- consistent with clinical reports of uncontrolled open-label tative antipsychotic medications are listed in Table 1. Lox- successes with loxapine added to existing first-line atyp- apine is intermediate between standard neuroleptics and ical antipsychotic therapy (e.g., olanzapine, risperidone, second-generation atypical antipsychotics with regard to quetiapine) at San Antonio State Hospital, suggesting a serotonergic activity vis-á-vis dopaminergic effects. As role for low-dose adjunctive loxapine therapy (10Ð50 demonstrated in Table 1, loxapine’s metabolites variably mg/day) in partially responding patients. Further clinical demonstrate potentially significant 5-HT2A receptor block- improvement from baseline with minimal impact on EPS ade compared with haloperidol. These data, based on Kd, is observed as the result of this approach. A similar ap- need to be interpreted within the context of other studies proach has been suggested for risperidone as adjunctive that evaluate functional receptor antagonism by the test therapy; a well-described case series using risperidone drug including potential partial agonist activity and that

J Clin Psychiatry 1999;60 (suppl 10) 23 Larry Ereshefsky

Table 2. Potency of Loxapine and Metabolites Compared With Figure 5. Hypothetical Loxapine Daily Dose (at steady state) Imipramine as Inhibitors of the Norepinephrine (NE) and Versus Pharmacologic Effectsa Serotonin (5-HT) Transportersa NE Transporter 5-HT Transporter Partial atypicality range Inhibition Inhibition High

Drug/Metabolite (IC50 nM) (IC50 nM)

Loxapine None None D2 blockade D4 blockade Amoxapine 22.5 566 5-HT2A blockade 7-Hydroxyamoxapine 16.6 424 8-Hydroxyamoxapine 33.8 323 Imipramine 16.8 55.8 α blockade a Data from reference 18. Abbreviation: IC50 = concentration at which transporter uptake© functionCopyright is inhibited by 50%2000 from baseline. Physicians Postgraduate Press, Inc.

Inhibition of Relative Effect biogenic amine transporter use behavioral models presumed to be specific for D2 or 47 5-HT2 effects. In vivo functional studies are needed to Muscarinic blockade validate loxapine’s potential atypical profile, given clini- Low cal data which suggest that loxapine does not approximate 0 25 50 100 150 200 > 250 Loxapine Daily Dose, mg risperidone in usual practice. Moreover, binding affinity to receptors does not fully characterize a drug’s pharmacol- aThis figure represents the author’s conceptualization of observed ogy, since protein binding, metabolite concentrations at the effects from clinical use of loxapine. Where dopamine receptor blockade of the type 2 and 4 receptors along with serotonin-2A site of action, and differing duration of binding time to re- receptor blockade are the most potent effects resulting from loxapine One personal copy mayadministration. be printed Intermediate doses produce α-adrenergic blockade. ceptors are not estimated. Additionally, D4 receptor block- Higher doses begin to engage biogenic amine transporter inhibition ade for loxapine is highly potent, greatly exceeding the and antimuscarinic effects. binding affinities of most neuroleptics, a property shared with clozapine.48,49 Table 2 lists in vitro data which demonstrate that loxapine and its metabolites are potentially finity of the drug or metabolites for the receptor; antidepressants based on their potency to inhibit the nor- and adrenergic transporter.18 Based on positron emission to- 6. The “net” pharmacologic effects are influenced by mography (PET) data, 5-HT2A and D2 receptor blockade the relative concentrations of loxapine and its me- are maximally effected at doses of less than 100 mg/day,34 tabolites. suggesting a usual dosage range maximum that is consid- erably lower than the labeled dosing range of up to 250 CLINICAL IMPLICATIONS mg/day. At doses exceeding 100 mg/day, it is likely that α antimuscarinic, -adrenergic, and other less potent phar- The importance of dosage for drugs with 5-HT2A/D2 ra- macologic effects begin to “catch up” with the more potent tios in an intermediate range, e.g., ≈ 1.15 as listed in Table pharmacologic effects that have already reached their 1, is illustrated by 2 recent comparative trials with risperi- maximum effect at lower doses (Figure 5). done and olanzapine. Risperidone at an average dose of just The author’s conceptualization of pharmacologic ef- over 8 mg/day has been demonstrated to cause significantly fects differs from Richelson’s binding studies12 in the fol- more EPS (and other adverse effects) when compared in a lowing ways: double-blind trial with olanzapine at an average dose of 18 mg/day.50 Some advantages in efficacy as demonstrated by 1. There is substantial variability in receptor binding mean change from baseline on the Positive and Negative constants from laboratory to laboratory7,8,22; Symptom Scale (PANSS) were suggested for the olanza-

2. D2 blockade appears to dominate as dose is in- pine treatment group. In contrast, the interim results of a creased, e.g., EPS observed despite more potent recent study51 evaluating risperidone at an average dose of

5-HT2 blockade; 4.8 mg/day demonstrated no statistically significant differ- 3. Steady-state concentrations of loxapine plus me- ences in EPS versus olanzapine. Therapeutic equivalency

tabolites result in D2 blockade dominance at com- based on the mean change from baseline for the PANSS monly used doses, e.g., loxapine, 50 mg/day; (with some subanalyses suggesting superiority for risperi-

4. Functional integration of all effects, e.g., D2, done) following 8 weeks of treatment document the factor α 5-HT2, and 1 blockade and norepinephrine reup- dosage plays in obtaining maximum benefit from risperi- take inhibition, explains clinically observed ef- done.51 The determination of minimum dosage for drugs

fects; with potent D2 receptor antagonist properties is of great in- 5. The duration of binding to the D2 receptor may terest, although few placebo-controlled trials with fixed- vary widely and not in direct proportion to the af- dose paradigms utilize neuroleptic threshold dosing. One

24 J Clin Psychiatry 1999;60 (suppl 10) Pharmacologic and Pharmacokinetic Considerations

Figure 6. Percentage of Phase 1 Male Volunteers With Any placebo-controlled clinical trials. Hypotension was re- Manifestations of EPS Following Single Doses of Loxapine ported in 23% of the patients receiving doses of 10 to 120 (over 24 hours)a mg daily in divided doses for periods of up to 13 weeks.55 100 Cardiovascular symptoms including tachycardia, syncope, 90 and dizziness were reported in 11 of 20 patients receiving 80 mean doses of 87.5 mg of loxapine daily over a period of 3 70 weeks.56 Patients develop tolerance to hypotension, fur- 60 50 ther emphasizing the need to initiate therapy at lower α 40 doses, e.g., 10Ð25 mg/day. -Adrenergic blockade is con-

% of Patients 30 sidered to be part of the pharmacologic profile that lends 20 © Copyright 2000 Physiciansrisperidone Postgraduate and quetiapine their Press, atypicality. Inc. 10 Given the broad spectrum of pharmacologic effects at- 0 Placebo 15 mg 25 mg 30 mg 50 mg 100 mg 150 mg tributed to loxapine, its potential as monotherapy for Loxapine Dose mixed anxiety and depression and for neurosis and anxiety aData from reference 17. has also been explored, although use of this medication in nonpsychotic disorders is discouraged.57Ð59 Loxapine has been reported to be potentially useful in psychotic depres- recent study incorporated 3 fixed-dose treatment arms for sion, either when given alone or in conjunction with haloperidol (4, 8, and 16 mg/day) against placebo and ser- amoxapine.60,61 Olanzapine and clozapine, both structur- tindole. These doses of haloperidol demonstrated excellent ally related to loxapine, have recently demonstrated clini- clinical efficacy based on the mean change from baseline cal utility in relieving depressive symptoms in schizo- on the PANSS. The modest improvementsOne personal observed copy in mayphrenic be printedpatients. Interestingly, there is a case report of a negative symptoms using the Scale for the Assessment of possible manic “reaction” to loxapine in the literature.62 Negative Symptoms (SANS), rather than worsening, un- Given the moderate sedative properties of loxapine, it is derscore the need for lower than previously appreciated not necessary to coadminister benzodiazepines with it, doses of neuroleptic. However, even at these lower doses, even in the most extreme cases of aggression.25 In fact, e.g., 4 mg/day of haloperidol, significant EPS were present caution should be exercised in coadministering lorazepam when compared with sertindole.52 The intermediate potency and loxapine, since a case report suggests that increased profile of loxapine for D2 blockade is associated with lower intensity of central nervous system (CNS) depressant ef- rates of EPS than is the profile of haloperidol when utilized fects and hypotension might occur.63 Interestingly, a simi- in dose ratios of ≤ 10 mg of loxapine equivalent to 2 mg of lar reaction is reported to occur with benzodiazepine coad- haloperidol.37,38,53 Moreover, the possible beneficial effects ministration during the early stages of clozapine therapy. of loxapine on negative symptoms via 5-HT2A blockade de- Phase 1 clinical data evaluating single doses of loxa- serve further clinical exploration. pine in normal healthy volunteers is displayed in Figure Loxapine and its metabolites, in addition to their dopa- 6.17 These data demonstrate an intriguing dose-response minergic and serotonergic effects, can bind other receptors relationship for EPS that further supports the potential ad- that mediate both potential benefits and adverse reactions. vantages of low-dose loxapine. Single dosages in the 15 to Additionally, loxapine’s metabolites, e.g., amoxapine and 30 mg range demonstrated the same rate of EPS as place- 8-hydroxyamoxapine, are reasonably potent inhibitors of bo. The rate of EPS at 50 mg/day was intermediate, while the noradrenergic transporter protein responsible for reup- doses ≥ 100 mg/day demonstrated the expected rate of take, lending loxapine potential antidepressant and anxio- EPS observed in most phase 1 studies of ≥ 50%. Taken lytic properties.18 Figure 5 illustrates hypothetical dose- collectively, the clinical studies, PET and in vitro receptor versus-response relationships for loxapine at the D2, D4, binding data, and pharmacologic dosing considerations α 5-HT2A, -adrenergic, and muscarinic receptors as well as suggest potential utility for loxapine as an alternative the potential for antidepressant-like activity by inhibition treatment in patients with persistent psychotic disorders of the noradrenergic transporter. The interplay of these and as adjunctive therapy in combination with atypical pharmacologic effects suggests that an optimum dosage of antipsychotics. Low-dose adjunctive loxapine therapy in loxapine, based solely on D2 receptor considerations, combination with atypical agents could add D2 blockade ≤ should be 50 mg/day in most subjects (adjusted based on while maintaining an overall favorable 5-HT2/D2 blockade drug interactions and response).34,54 When one factors in ratio. the potential contributions for its 5-HT2A and possibly ad- Higher doses of loxapine are more clearly classically renergic blocking effects, lower doses could very well be neuroleptic, and neuroleptic malignant syndrome and tar- effective for the long-term maintenance of schizophrenia. dive dyskinesia occur with this medication.64 However, at Clinical evidence supporting α-adrenergic blocking ef- the highest doses studied (≥ 250 mg/day), clinical re- fects at doses within the therapeutic range come from sponse in previously neuroleptic-resistant patients and

J Clin Psychiatry 1999;60 (suppl 10) 25 Larry Ereshefsky

Figure 7. Intramuscular Loxapine Normalized to 25-mg Dose Figure 8. Oral Loxapine Normalized to 25-mg Dose (pooled (pooled data, N = 10)a data, N = 11)a

35 20 Loxapine 18 Loxapine 30 8-Hydroxyloxapine 8-Hydroxyamoxapine 16 8-Hydroxyloxapine 8-Hydroxyamoxapine 25 7-Hydroxyloxapine 14 12 20 10

ng/mL 15 ng/mL 8 10 6 4 © Copyright 2000 Physicians Postgraduate5 Press, Inc. 2 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Hour Hour aData from references 14, 68, and 69 and L.E., unpublished data from aData from references 14, 68, and 69 and L.E., unpublished data from the Therapeutic Drug Monitoring Program of San Antonio State the Therapeutic Drug Monitoring Program of San Antonio State Hospital and Texas Institute of Mental Sciences, 1982Ð1985. Hospital and Texas Institute of Mental Sciences, 1982Ð1985. 7-Hydroxyloxapine quantitated in 5 subjects. control of dangerous aggression in forensic patients have few minutes to hours following ingestion or injection of been demonstrated.41 Perhaps at the highest doses, other the medication.66 As active metabolites are produced, the effects on CNS neurotransmission areOne significant, personal contrib- copy maypharmacologic be printed profile can become a hybrid of all active uting to efficacy, e.g., α-blockade, antimuscarinic, and moieties in the body and the brain. The pharmacokinetics aminergic transporter inhibition. These doses are not rou- of the parent and active metabolite(s) define the net con- tinely recommended, since control of aggression can be centrations and brain exposures to the medications. Fol- more specifically managed with mood-stabilizing agents, lowing oral administration of loxapine, the onset of seda- while treatment-resistant patients have a wide variety of tion is within 30 minutes, and peak concentrations of better-tolerated novel agents available. parent drug are observed within 1.5 to 3 hours.14,17,67 Addi- As a result of the increasingly divergent pharmacology tionally, the rate of metabolism upon initial dosing is in- of antipsychotic drugs, it is necessary to reconceptualize fluenced by the route of administration. Since the bio- our views about dose-versus-response relationships since availability of loxapine is approximately 33% based on an multiple pharmacologic effects contribute to the therapeu- evaluation of a single dose of 25 mg i.m. versus oral con- tic endpoint. Each pharmacologic effect is likely to dem- centrate performed in male volunteers, first-pass metabo- onstrate a distinct dose (or concentration)-versus-response lism following oral administration plays an important role, relationship, or more directly, receptor concentrationÐ i.e., a high-extraction drug defined by 1 Ð F (bioavailabil- versus-effect relationship. If a pharmacologically complex ity) = 67%. Plasma concentrations obtained during this drug is studied, e.g., loxapine, then one must evaluate dos- bioavailability study demonstrated that single doses of in- age within the context of dopamine-related effects, sero- tramuscular loxapine produce lower concentrations of tonergic effects, α-adrenergic blocking effects, biogenic 7- and 8-hydroxyloxapine and 7- and 8-hydroxyamoxa- amine transporter inhibitor effects, and their interaction pine67 than does oral therapy. Plasma levels of 8-hydroxy- with each other. Perhaps the dosage needed for response loxapine rapidly rise to levels significantly greater than will be different for patient subpopulations (e.g., positive those of loxapine within a few hours following a single symptomÐ versus negative symptomÐdominant clinical oral dose. In contrast, after an intramuscular dose, concen- presentation or treatment-refractory versus first-break pa- trations of the parent drug predominate and rise more tients).3,65 Therefore, the best possible outcomes in treating slowly than with the oral dose, but the concentrations of schizophrenia with loxapine are likely to result from a the metabolites remain lower than parent concentrations slow, gradual titration of dosage, ensuring sufficient time for the first 12 to 16 hours.68 at each dosage step. Although there are limited published pharmacokinetic data from patients treated at usual doses of loxapine, a few PHARMACOKINETIC CONSIDERATIONS investigations were completed in the early 1980s. Figures FOR LOXAPINE THERAPY 7 and 8 illustrate mean concentrations of loxapine, 8-hydroxyloxapine, and 8-hydroxyamoxapine following In single doses, the pharmacologic profile of an anti- intramuscular and oral single doses of loxapine with the psychotic drug is usually defined by the parent molecule dose normalized to 25 mg (references 14, 68, and 69 and (unless a pro-drug). This is especially true during the first L.E., unpublished data from the Therapeutic Drug Moni-

26 J Clin Psychiatry 1999;60 (suppl 10) Pharmacologic and Pharmacokinetic Considerations

Table 3. Pharmacokinetic Summary of Loxapine and Its metabolite). Although the pharmacokinetic profile for lox- Metabolitesa apine and its metabolites is not completely characterized, Mean ± SD Predicted some plasma concentration data for the complete constel- Mean Steady-State Concentrations lation of molecules of interest are available at steady Half-Life, h Concentrations, at Steady State, 14,54,69 Drug or Metabolite (range) ng/mLb ng/mLc state. With chronic dosing, the greatest accumulation Loxapine 3.4(2.4Ð8.1) 24 ± 14 12 (Table 3) will occur with hydroxy metabolites. The Amoxapine 8 (5Ð14) 12 ± 9 Not evaluated 7-hydroxyamoxapine, in particular, has been identified as 8-Hydroxyloxapine 9 (6.4Ð22) 90 ± 76 33 the likely source of neuroleptic effects when amoxapine is 7-Hydroxyloxapine 6.5(4Ð11) 8.4 ± 84 18 8-Hydroxyamoxapine 35 (30Ð48) 49.3 ± 42 Not evaluated administered. Its potency for D2 blockade is comparable 7-Hydroxyamoxapine Not known 3.1 ± 2.5 Not evaluated with haloperidol’s potency,71 and it demonstrates the low- a © Copyright 2000 Physicians Postgraduate Press, Inc. Data from reference 34 and the Therapeutic Drug Monitoring Program est 5-HT2A/D2 affinity ratio in human receptor binding with the Texas Research Institute of Mental Sciences, unpublished studies.12 Clinically observed cases of EPS with amoxa- data, 1983Ð1988. bConcentrations in patients (N = 10) from San Antonio State Hospital pine correlate with 7-hydroxy metabolite production (1983Ð1988) normalized to 50 mg/day. (L.E., review of unpublished amoxapine case surveillance cPredicted concentrations for 50 mg/day of loxapine at steady state. Regression is based on 10 patients, of whom 7 had dosages at data at Lederle Laboratories [M. Bishop, Ph.D.], Pearl < 25 mg/day. One patient with a dosage of 100 mg/day had River, N.Y., 1983). The antidepressant effects of loxapine concentrations of 39.4, 9.0, and 89.4 ng/mL of loxapine, 7-hydroxyloxapine and 8-hydroxyloxapine, respectively. are in part the result of production of amoxapine and 8-hydroxyamoxapine.72Ð74 The production of 7-hydroxyloxapine and 7-hydroxyamoxapine potentially reduces the toring Program of San Antonio State Hospital and Texas serotonergic effects of therapy at steady state. However, Institute of Mental Sciences, 1982Ð1985). Additionally, the concentrations of these 2 metabolites from low-dose 7-hydroxyloxapine plasma concentrationsOne personal were measur- copy mayloxapine be printed therapy are modest.16 able in 5 subjects following oral therapy. These data demonstrate for intermittent (p.r.n.) intramuscular administra- DRUG-DRUG INTERACTIONS tion of loxapine a different pharmacokinetic profile for parent versus metabolite concentrations as compared with Drug metabolism for most antipsychotics including oral dosing conditions. Loxapine as a p.r.n. adjunctive phenothiazine antipsychotics, dibenzoxazepines and their therapy in the management of acute agitation, aggression, structural analogs (e.g., loxapine, olanzapine, and cloza- or hostility could result in effective control of symptoms pine), and others (e.g., quetiapine and risperidone) is with some atypical antipsychotic attributes, e.g., less EPS highly variable, resulting in at least 4-fold but usually potential due to the higher 5-HT2A/D2 affinity ratios for 10-fold or greater intersubject variability in concentrations loxapine than its 7-hydroxy metabolites. Loxapine as ad- from a fixed dose.75Ð78 The variability is in part attributed junctive intramuscular therapy might be less likely to up- to intrinsic heterogeneity in drug metabolism and bioavail- set the serotonergic-to-dopaminergic balance of atypical ability, as well as extrinsic factors such as drug-drug inter- antipsychotics in patients during the crisis intervention actions, cigarette smoking, and comorbid medical condi- stage of therapy or whenever exacerbation of psychosis or tions. Even if a precise therapeutic range cannot be aggression occurs. Clinical trials conducted with this determined, the fact that plasma concentrations can span medication clearly demonstrate its rapid onset and utility the nonmeasurable to toxic range at usual doses suggests as an intervention to manage psychiatric emergencies; utility in identifying, a priori, outlying patients who need however, minimum effective doses of loxapine that might major dosage adjustments to approximate usually effective maximize benefit versus EPS have not been evaluated.14 therapy.70,78,79 A patient previously stabilized on a dosage When medications are administered on a continuing of antipsychotic may need to have that dosage readjusted basis by the oral route, plasma concentrations are noted to whenever other medications are indicated and coadminis- gradually increase over the time course of therapy. This tered.80Ð83 Drug interactions must be factored into the dos- increasing plasma concentration over time can be modeled ing strategy for patients receiving psychotropic medica- and predicted by applying the concept of steady state. tions, especially when 2 or more antipsychotic medications Steady state is obtained when the amount of drug deliv- and other adjunctive therapies are combined.84 The transi- ered to the systemic circulation is equal to the amount of tion from one drug to another requires substantial overlap- drug being eliminated from the body. Therefore, it is an ping therapies in most patients. Is the “transient” improve- equilibrium state where the input and output functions for ment observed during overlap of 2 therapies a result of drug are balanced.70 The time required to attain steady- pharmacodynamic or pharmacokinetic interactions or state plasma concentrations is approximately 5 times the both? The apparent worsening of patients once the transi- drug’s half-life. Similarly, metabolites build to steady tion is completed from old to new antipsychotic therapy state as an equilibrium point is reached between input can in part be explained by the restoration of drug metabo- (metabolism of the parent) and outflow (clearance of the lism once an inhibitor is stopped. To address this issue,

J Clin Psychiatry 1999;60 (suppl 10) 27 Larry Ereshefsky many of the case studies cited above measured plasma average, change the concentrations of thiothixene by concentrations of clozapine when either loxapine or risper- greater than a factor of 5, if the neuroleptic dose is held idone was added, demonstrating no significant pharmaco- constant.82 Although drug interaction data for loxapine are kinetic effects. Isolated cases of elevated concentrations of very limited, based on the structural similarities of loxa- clozapine have been reported, however, with the addition pine to olanzapine and clozapine, it is likely to utilize the of risperidone, suggesting that a definitive answer regard- same cytochrome P450 pathways, although the relative ing these drug interactions is lacking.85 The systematic extent through each pathway will be unique for each drug. study of drug-drug interactions during and following com- An important environmental influence on antipsychotic bination therapy should be incorporated into clinical trials drug clearance is cigarette smoking, including passive in- studying this important strategic intervention. halation of smoke.88 Inhaled smoke induces CYP1A2 en- Since loxapine© Copyright partially shares pharmacologic2000 Physicians proper- zymatic Postgraduate activity, increasing systemic Press, metabolic Inc. clearance ties with the atypical antipsychotic risperidone, whereas rates, resulting in significant drug interactions. Mean de- the 7-hydroxy metabolites might be less atypical, drug creases in plasma concentrations of thiothixene, haloperi- interactions could alter the ratio of parent-to-metabolite dol, and fluphenazine range between 20% to 100%.82,88,89 concentrations in plasma and shift the balance away from Clozapine and olanzapine, structurally most similar to lox- serotonergic and toward dopaminergic blockade. Potent apine, also demonstrate increased metabolic clearance cytochrome P450 2D6 (CYP2D6) inhibitors, e.g., paroxe- rates of 20% to 50% greater than baseline in smokers.78 tine and fluoxetine, and/or CYP3A4 inhibitors, e.g., nefa- The literature also describes case reports in which patients zodone and erythromycin, might increase the steady-state develop adverse effects while maintaining a constant dose loxapine:7-hydroxyloxapine, loxapine:8-hydroxyloxapine, of antipsychotic secondary to voluntary cessation of and loxapine:7-hydroxyamoxapine ratios.84 It is possible smoking.90 Therefore, dosing of antipsychotic medications that combined therapies with CYP inhibitorsOne personal could alter copy the mayrequires be printed careful monitoring and slow titration from mini- pharmacologic effects of loxapine, increasing the apparent mum effective doses since interpatient variability reduces atypicality of the intervention. Similarly, those patients the success rate for any fixed-dose strategy. with genetic polymorphism at CYP2D6 for poor metabo- lizer status will also likely demonstrate significantly greater SUMMARY loxapine than hydroxy metabolite concentrations.86 Clini- cal observation of patients for changes in EPS and efficacy Loxapine is pharmacologically and pharmacokinetically for negative symptoms should be closely monitored when a complex drug. It appears to fall somewhere between ha- potentially interacting drugs are either started or stopped. loperidol and risperidone in terms of relative affinities for

Additionally, potent CYP1A2 inhibitors (e.g., fluvoxamine D2 versus 5-HT2A receptors. However, loxapine’s neuro- α and fluoroquinolone antibiotics) might reduce the forma- chemical profile also includes D4 blockade, 1 and musca- tion of amoxapine (demethylation) and its downstream hy- rinic-1 (M1) receptor blocking effects, and noradrenergic droxy metabolites. This could conceivably lessen the anti- transporter inhibition (at higher doses). These are proper- depressant and anxiolytic potential of treatment. Studies are ties shared with other dibenzoxazepine derivatives, e.g., needed to validate these suggested implications. clozapine and olanzapine. Based on these considerations, Reduction of plasma antipsychotic concentrations can low doses of loxapine could more closely resemble an α occur through the use of anticonvulsant medications, par- atypical antipsychotic profile, e.g., 5-HT2A +D2 + 1 block- ticularly carbamazepine,78,82,83 phenobarbital, phenytoin,87 ade. As the dose is increased, especially with chronic and from any other drug or condition that might induce therapy, D2 receptor blockade will increase to a greater ex- microsomal enzymes, e.g., subchronic ingestion of etha- tent, while 5-HT2A blockade will have already reached its nol. To illustrate the magnitude of the metabolic shift ob- asymptotic maximum effect at lower doses. This might be served as a result of drug interactions, a naturalistic study in part due to the production of 7-hydroxy metabolites of of thiothixene demonstrated dramatic changes in metabol- loxapine that have a pharmacologic profile more similar to ic clearance secondary to drug interactions.82 There was, that of haloperidol. α-Adrenergic blockade occurs at low on average, a greater than 3-fold difference in clearance doses, increases in a dose-related fashion, and probably rate if one compares steady-state concentrations in pa- contributes to both efficacy and side effects. At higher tients taking no interacting medications versus those tak- doses, antidepressant and antimuscarinic effects might being enzyme inducers. Therefore, it will require 3 times as come significant, lending utility for selected treatment- much thiothixene to achieve the same plasma concentra- refractory patients. The literature supports reduced rates of tion in the drug interaction group as in those patients re- EPS compared with haloperidol when low doses (< 50 mg) ceiving no concomitant medications. of loxapine are used. The intramuscular dosage form, lox- Conversely, adding enzyme inhibitors to thiothixene apine succinate, might be particularly useful as an emer- results in a greater than 2-fold reduction in clearance. gency intervention in managing positive symptoms, given Switching from enzyme inducer to inhibitor will, on the the absence of first-pass metabolism, resulting in greater

28 J Clin Psychiatry 1999;60 (suppl 10) Pharmacologic and Pharmacokinetic Considerations concentrations of loxapine than metabolites when com- performance liquid chromatography. J Chromatogr 1991;564:213Ð221 16. Dahl SG. Active metabolites of neuroleptic drugs: possible contribution to pared with oral therapy. therapeutic and toxic effects. Ther Drug Monit 1982;4:33Ð40 The use of loxapine as adjunctive therapy in combina- 17. Loxitane: Loxapine Succinate. Pearl River, NY: Medical Advisory Depart- tion with an atypical antipsychotic is theoretically interest- ment, Lederle Laboratories; 1975:1Ð95 18. Coupet J, Rauh CE, Szues-Myers VA, et al. 2-Chloro-11-(1-piperazinyl) ing and supported by limited case and anecdotal literature. dibenz[b, f] [1, 4]oxazepine (amoxapine), an antidepressant with antipsy- Loxapine might be a good choice to add when treating par- chotic properties: a possible role for 7-OH-amoxapine. Biochem tially responding schizophrenic patients already stabilized Pharmacol 1979;28:2514Ð2515 19. Beasley CM Jr, Tollefson G, Tran P, et al, and the Olanzapine HGAD Study on treatment with atypical antipsychotic agents. It is pos- Group. Olanzapine versus placebo and haloperidol: acute phase results of sible, although not documented, that the addition of loxa- the North American double-blind olanzapine trial. Neuropsychopharma- pine or another antipsychotic drug to existing regimens of cology 1996;14:111Ð123 © Copyright 2000 Physicians20. OwensPostgraduate MJ, Risch SC. Atypical Press,antipsychotics. Inc.In: Schatzberg AF, more expensive therapies, e.g., olanzapine, risperidone, or Nemeroff CB, eds. The American Psychiatric Press Textbook of Psycho- quetiapine, could “dose-spare” these atypicals, resulting in pharmacology. 2nd ed. Washington, DC: American Psychiatric Press; equivalent efficacy at less cost. This increased efficiency 1998:323Ð343 21. Reynolds GP, Czudek C. 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