CHAPTER TEN
Clinical Pharmacology of Dopamine-Modulating Agents in Tourette’s Syndrome Sabine Mogwitz, Judith Buse, Stefan Ehrlich, Veit Roessner1 Department of Child and Adolescent Psychiatry, University Medical Center, Technische Univerita¨t Dresden, Dresden, Germany 1 Corresponding author: e-mail address: [email protected]
Contents 1. Introduction 1.1 The role of dopamine in treatment of TS 2. DA Receptor Antagonists 2.1 Introduction 2.2 The mechanism of action 2.3 Adverse effects 2.4 Specific concerns during fertility stage 2.5 Interactions 2.6 Monitoring 3. Systematic Review of Dopamine Receptor Antagonists in the Treatment of TS 3.1 Typical antipsychotics 3.2 Atypical antipsychotics 3.3 Benzamides 4. Tetrabenazine 4.1 Studies on the effectiveness of tetrabenazine in the treatment of TS 4.2 Characteristic adverse effects of tetrabenazine 5. Dopamine Agonists 5.1 Studies on the effectiveness of dopamine agonists in the treatment of TS 5.2 Characteristic adverse effects of dopamine agonists 6. Summary References
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Abstract Forty years of research and clinical practice have proved dopamine (DA) receptor antagonists to be effective agents in the treatment of Tourette’s syndrome (TS), allowing a significant tic reduction of about 70%. Their main effect seems to be mediated by the blockade of the striatal DA-D2 receptors. Various typical and atypical agents are available and there is still discord between experts about which of them should be
International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00010-X
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2013 Elsevier Inc. All rights reserved.
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considered as first choice. In addition, there are suggestions to use DA receptor agonists such as pergolide or non-DA-modulating agents. The present chapter is focusing on the clinical pharmacology of DA-modulating agents in the treatment of TS. The introduction outlines their clinical relevance and touches on the hypotheses of the role of DA in the pathophysiology of TS. Subsequently, general information about the mechanisms of action and adverse effects are provided. The central part of the chapter forms a systematic review of all DA-modulating agents used in the treatment of TS, including an overview of studies on their effectiveness, and a critical discussion of their specific adverse effects. The present chapter closes with a summary of the body of evidence and a description of the resulting recommendations for the pharmacological treatment of TS.
1. INTRODUCTION Tics and tic-related behavioral symptoms can have a major impact on the patient’s performance at school and work and they can lead to social difficulties (Roessner et al., 2011). Quality of life was found to be significantly worse in patients with Tourette’s syndrome (TS) compared to healthy controls with tic severity being a usable predictor of quality of life (Cutler, Murphy, Gilmour, & Heyman, 2009). Individual treatment of a patient should be planned by considering the available diagnostic information, the level of the patient’s impairment, the effectiveness and tolerability of the treatment options, as well as the patient’s preference (Pringsheim et al., 2012; Roessner et al., 2011). If the benefit of behavioral therapy is not sufficient, pharmacotherapy should be added or should replace the previous treatment—always in combination with psychoeducation (Roessner et al., 2011). In severe cases with strong psychosocial impairment, poor coping or no availability of specialized behavioral therapy, initiation of pharmacological treatment might be considered right at the beginning (Roessner et al., 2011). Although pharmacotherapy of tics is the fastest and most promising treatment option (Roessner et al., 2011), pharmacological treatment is symptomatic, which means it improves the tics at best, but does not cure them (Gilbert, 2006). Additionally, there is no evidence yet that a short- to intermediate-term medication influences the natural long-term prognosis of tic symptoms, that is, there is no evidence that refraining from any treatment has negative consequences on the course of the disorder. Therefore, a watchful waiting does not necessarily imply having missed an important chance (Rothenberger & Roessner, 2013).
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Scientific evidence for the effectiveness of different pharmacological treatment options based on randomized, controlled trials is limited (Roessner et al., 2011). Especially studies meeting stringent methodological criteria and taking the effect of tic severity, comorbidities, and comedication into account are missing (Roessner, 2012). A particular difficulty in the evaluation of treatment options in TS is its waxing and waning course, that is, the fluctuation of frequency, intensity, location, and complexity of tics over time (Leckman, 2002). In addition to these “natural” changes of unknown cause over time, the modulating influence of environmental and/or psychosocial factors, such as stress, excitement, anxiety, anger, fatigue, concentration, and activity must be considered in order to judge the effectiveness of a certain treatment correctly (Roessner et al., 2011). Consequently, results of the two Cochrane reviews on pharmacological treatment of tics in TS (Curtis, Clarke, & Rickards, 2009; Pringsheim & Marras, 2009) concluded that the existing evidence for the effectiveness and safety of the studied drugs does not allow clear recommendations (Roessner et al., 2011). Long-term trials with larger groups of TS patients using the Yale Global Tic Severity Scale (YGTSS) as the primary outcome measure and standardized rating scales to assess adverse effects such as the Extrapyramidal Symptom Rating Scale are needed. Nevertheless, 30 years of experience with treatment of TS have established a number of pharmacological agents as promising first-line treatment for TS. However, the huge variety of substances used indicates that none of them is ideal, and none of them provides complete relief without adverse effects in all patients (Roessner et al., 2011).
1.1. The role of dopamine in treatment of TS Almost since the beginning of research on TS, tics have been associated with a dysfunction of the dopamine (DA) system. For a long time this assumption was mainly based on clinical findings of DA receptor antagonists (DARA) being the most effective drugs in treating tics with a marked decrease of tics in about 70% of cases (Shapiro & Shapiro, 1998). In recent years, nuclear imaging has allowed a much deeper understanding of DA neurotransmission. Based on the findings of various positron emission tomography (PET) and single-photon emission computer tomography (SPECT) studies, four hypotheses on DA dysfunction in TS are discussed: (1) DA hyperinnervation, (2) supersensitive DA receptors, (3) presynaptic DA abnormality, and (4) DA tonic–phasic dysfunction (Buse, Schoenefeld, Mu¨nchau, & Roessner, 2013; Singer, 2013).
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Beside the apparent evidence for deviances in the DA system, suggestions concerning imbalances in other neurotransmission systems like the serotonergic, the noradrenergic, the glutamatergic, the GABAergic, the cholinergic, and the opioid system have been made (Harris & Singer, 2006; Swain, Scahill, Lombroso, King, & Leckman, 2007).
2. DA RECEPTOR ANTAGONISTS 2.1. Introduction “DA receptor antagonism” describes a pharmacodynamics feature of various agents used for numerous indications. In fact, all antipsychotics show some DA receptor antagonism (Patteet et al., 2012).1 A distinction is made between agents designed before the 1980s, called first-generation antipsychotics and the drugs designed more recently, defined as second-generation antipsychotics. Since the latter are assumed to cause less extrapyramidal motor symptoms (EPS) they are called atypical antipsychotics (AA) compared to the first-generation antipsychotics which are considered to cause “typical” adverse effects and are therefore called typical antipsychotics (TA). But in fact, the differentiation between the TA and AA is not always that clear (Almandil & Wong, 20111; Moleman, 20091). Since their introduction in the 1950s antipsychotics are mostly used to treat schizophrenia and schizoaffective disorders (Patteet et al., 2012).1 But since 40 years studies of different quality have proved antipsychotics to be also effective in reducing tics to a significant degree (Mu¨ller-Vahl, 2007; Shapiro & Shapiro, 1998; Silay & Jankovic, 2005; Singer, 2000). Recent reviews and guidelines on pharmacological treatment of TS recognized DARA as the most effective pharmacological treatment for tics (Roessner et al., 2011, 2013; Weisman, Qureshi, Leckman, Scahill, & Bloch, 2012), but also alpha-2 agonists including clonidine and ganfacine are often stated as the first-line pharmacological treatment, because of their more benign safety profile (Pringsheim et al., 2012). However, recommendation of the latter ones is questioned by recent meta-analytic findings that the modest but significant benefit of alpha-2 agonists in the treatment of children with TS is mainly moderated by its impact on comorbid attention deficit hyperactivity disorder (ADHD) and that in the absence of ADHD,
1
Publications not primarily focusing on tics and/or Tourette’s Syndrome (TS) (publications on tics and/or TS are not marked).
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however, the efficacy of these agents was small and nonsignificant (Weisman et al., 2012). Overall, there is still discord between experts about the first-choice agent due to the deficient body of evidence, regional differences, and personal experience (Roessner et al., 2011). Due to the fluctuating symptomatology only with the help of double-blind, placebo-controlled studies of longer duration, a sufficient statement about the efficacy of agents in the treatment of TS can be made (Mu¨ller-Vahl, 2007).
2.2. The mechanism of action Antipsychotics influence the synaptic gateways in the brain by influencing the transfer of DA. The mechanism on which they act is DA receptor antagonism (Patteet et al., 2012).1 In fact, all antipsychotics block the consequences of the probably inappropriate presynaptic DA release (Howes & Kapur, 2009).1 TA show higher affinity for DA-D2 receptors than for DA-D1 receptors. AA, like sulpiride, can be highly selective for DA-D2 receptors, but others, like clozapine, are relatively nonselective for both DA-D1 and DA-D2 and highly selective for DA-D4 receptors (Rang, Dale, Ritter, & Moore, 2003).1 It can be stated: the stronger the potency of the DA blockade, the more effective is a drug in reducing psychotic syndromes as well as tics (Scahill et al., 2006). However, a strong blockade of DA receptors also correlates with the frequency of adverse effects, such as EPS (Bressan, Jones, & Pilowsky, 2004).1 Additionally, antipsychotics can also interact with receptors for serotonin, acetylcholine, histamine, and noradrenaline (norepinephrine) and thereby alter cholinergic, serotonergic, histaminergic, and alpha-adrenergic transmission (Roessner et al., 2013).
2.3. Adverse effects The use of antipsychotic agents seems to be a difficult trade-off between the benefit of reducing symptoms and the risk of troubling, sometimes even lifeshortening adverse effects (Muench & Hamer, 20101; Pringsheim et al., 2012). General adverse effects of antipsychotics due to their affinity to DA receptors are extrapyramidal motor symptoms (EPS) including Parkinsonlike symptoms such as tremor, akinesia, rigidity, and rabbit syndrome (a rare form of EPS characterized by involuntary, rhythmic motions of the mouth) but also dystonia, dyskinesia, and akathisia (Muench & Hamer, 2010).1
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Tardive dyskinesia (TD) is a serious and potentially irreversible adverse effect that can occur after longer treatment with antipsychotics. Several single case studies reported about TD in patients with TS (Golden, 1985; Riddle, Hardin, Towbin, Leckman, & Cohen, 1987; Silva, Magee, & Friedhoff, 1993), but a recent review raised doubts about the occurence of this severe side effect in patients with TS. Out of 521 patients treated with antipsychotics none ever developed TD. The rate of TD was significantly reduced compared to other psychiatric populations which led the authors to the assumption that TS might even prevent TD (Mu¨ller-Vahl & Krueger, 2011). In a review on motor side effects of antipsychotic use in children and adolescent, the prevalence rate of TD was found to be 1–5%, which is rather low compared to about 20% in adults (Wolf & Wagner, 1993).1 However, more often than TD, anxious/depressed symptoms such as shyness, lack of lust, avoiding school, and social withdrawal occur under treatment with haloperidol or pimozide (Linet, 1985; Mikkelsen, Detlor, & Cohen, 1981). Another common endocrine effect due to DA receptor antagonism is an increase of prolactin concentration associated with amenorrhea, erectile dysfunction (Muench & Hamer, 2010),1 infertility, and decreased libido (Freedman, 20031; Moleman, 20091; Sitsen, Cohen, & Franson, 20091). A rare but life-threatening complication is the neuroleptic malignant syndrome (NMS), characterized by muscle rigidity, rapid rise in body temperature, and mental confusion. It usually occurs with initiation of therapy or with dose adjustment. Incidence rates range from 0.02% to 3% among patients taking antipsychotics, whereas the risk is highest under treatment with TA. Death by renal or cardiac failure as a consequence of the NMS occurs in 10–20% (Levenson, 19851; Velamoor, 19981). Some antipsychotics cause a prolongation of the cardiac QT interval associated with an increased risk for “torsade de pointes” tachycardia, tachyarrhythmia, tachycardia, and sudden cardiac death (Blair, Scahill, State, & Martin, 20051; Glassman & Bigger, 20011; Muench & Hamer, 20101; Zareba & Lin, 20031). The greatest change in QT interval was seen under treatment with thioridazine (Glassman & Bigger, 2001).1 However, changes of the QT interval are often only relevant at toxic doses. The greatest risk is seen in women and elderly patients (Letsas et al., 2006) as well as in patients with concomitant cardiovascular pathologies, electrolyte imbalance (hypopotassemia and hypomagnesemia), hepatic or renal dysfunction, and coadministration of other drugs known to change the QT interval
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Figure 10.1 Overview of adverse effects caused by TA and AA in patients with tics. Halo, haloperidol; Ola, olanzapine; Clo, clozapine; Ris, risperidone; AA, atypical antipsychotics; TA, typical antipsychotics; Que, quetiapine; Ari, aripiprazole; Zip, ziprasidone.
(Moleman, 20091; Rettenbacher et al., 20051; Rizzo, Gulisano, Calı`, & Di Pino, 2013; Van Noord et al., 20091). Figure 10.1 shows common adverse effects of TA and AA and the agents causing them most frequently. 2.3.1 Adverse effects due to the affinity on serotonin receptors Blocking serotonin receptors can result in increased appetite and weight gain (Mathews & Muzina, 2007).1 2.3.2 Adverse effects due to the affinity on muscarinic acetylcholine receptors Blocking muscarinic acetylcholine receptors may lead to typical anticholinergic effects like blurred vision, increased ocular pressure, dry mouth and eyes, constipation, and urinary retention (Patteet et al., 2012).1
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2.3.3 Adverse effects due to the affinity on histamine-H1 receptors Drugs blocking histamine-H1 receptors are generally associated with weight gain (Czobor et al., 20021; Kroeze et al., 20031) or sedation (Patteet et al., 2012).1 Metabolic consequences, which might also occur without associated marked weight gain, include increased triglycerides, cholesterol, and glucose (Meyer, 2002)1; diabetes mellitus type 2 (Roessner et al., 2007); and secondary cardiovascular complications. Also, the possibility of an asymptomatic hypoglycemia during treatment has to be considered indicating a global disturbance of glucose metabolism (Budman, Gayer, Lesser, Shi, & Bruun, 2001). Given the potential metabolic side effects, regular controls of body weight, blood sugar levels, and serum lipids are recommended. 2.3.4 Adverse effects due to the affinity on a-adrenergic receptors Blocking a-adrenergic receptors can result in orthostatic hypotension (Patteet et al., 2012),1 sexual side effects, and nasal congestion (Mathews & Muzina, 2007).1
2.4. Specific concerns during fertility stage Beside decreased libido, a common adverse effect of TA and some AA, such as amisulpride and risperidone, is raised prolactin levels with the consequence of disturbances in menstrual cycle, gynecomastia, and galactorrhea. Although ethical reasons forbid studies with pregnant women, today systematically gathered knowledge on possible risks during pregnancy is available. Risperidone and quetiapine should be preferred during pregnancy due to their good tolerability and the number of documented uncomplicated pregnancies (Gentile, 20101; Reis & Ka¨lle´n, 20081; Rohde, Dorsch, & Schaefer, 20121). There are also several hundred reports about pregnancies under treatment with clozapine und olanzapine, but the associated hematologic and metabolic risks are critically discussed (Rohde et al., 2012).1 There are no signs for risk for the (unborn) child under treatment with amisulpride and ziprasidone either, but research data are scarce (Gentile, 20101; Reis & Ka¨lle´n, 20081). Due to warning results from animal studies, treatment in pregnant patients should not be initiated with aripiprazole but in cases a treatment with aripiprazole is already established a change of the agent with pregnancy onset is not always indicated (Gentile, 20101; Rohde et al., 20121). If antipsychotic treatment is administered until delivery, the newborn might exhibit transient adaptation problems like agitation, sedation, or drinking
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problems. Also, EPS might be observed in the newborn, especially if the mother has been treated with TA (Rohde et al., 2012).1 Since active substances of antipsychotics pass into breast milk, the common safety advice is that women treated with DARA should not breast feed. However, it is discussed as well whether the benefits of breastfeeding might outweigh the risks of exposing the babies to very low amounts of antipsychotic drugs (Te´nyi, Csa´bi, & Trixler, 2000).1
2.5. Interactions In clinical psychiatric practice comedication is often necessary, for example, in patients with comorbid psychiatric disorders or somatic diseases. Pharmacokinetic interactions can be observed if absorption, distribution, metabolism, or excretion of one drug is influenced by another. If two drugs interact at the same binding sites this might lead to additive, synergistic, or antagonistic effects. Most interactions with antipsychotics are associated with their metabolism, which is mediated by cytochrome P (CYP) enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) or uridine diphosphate glucuronosyltransferases (Spina & de Leon, 2007). Active metabolites, produced during elimination of antipsychotic agents can also inhibit CYP enzymes (Murray, 20061; Spina & de Leon, 2007). Selective serotonin reuptake inhibitor (SSRI) are able to cause a relevant inhibition of CYP enzymes (Spina & de Leon, 2007; Wille, Cooreman, Neels, & Lambert, 20081). Concomitant use of antipsychotics and dopaminergic medication, such as antiparkinsonism drugs and prolactin inhibitors, is not recommended because of their opposing effects (Patteet et al., 2012).1 Most antipsychotics can enhance central effects of other agents like central nervous system (CNS)-depressant drugs, antihypertensive drugs, and alcohol (Sweetman, 2007).1 The effect of antipsychotics can also be potentially reduced through co-consumation of coffee, black tea, some fruit juices, milk, antacid drugs, smoking (induction of enzymes), and anticonvulsants.
2.6. Monitoring A systematic anamnesis of the patient and a standardized assessment of the tic symptoms, for example, with the YGTSS are obligate. The clinical and neurological status prior to the first drug administration should be assessed to rule out existing contraindications for applying the chosen medication (Cath et al., 2011). Regular blood work is needed, especially blood sugar, liver and kidney parameters, blood cells due to the risk of low leukocytes, hyperglycemia, hypercholesteremia, hyperlipidemia, and hyperprolactinemia.
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An ECG to detect possible changes of the cardiac QT interval (risk of reentry tachycardia) should be conducted at least annually and is mandatory before starting the treatment (Rizzo et al., 2013; Roessner et al., 2011).
3. SYSTEMATIC REVIEW OF DOPAMINE RECEPTOR ANTAGONISTS IN THE TREATMENT OF TS 3.1. Typical antipsychotics TA are mainly used in the treatment of schizophrenia, because of their antipsychotic effect on positive symptoms (Patteet et al., 2012),1 but are also effective in the treatment of TS (Shapiro et al., 1989). Their effect is mainly due to a strong antagonism of DA-D2 receptors. The DA receptor occupancy is correlated with the antipsychotic potency but must also be seen as a predictor of adverse effects: a striatal DA-D2 occupancy of 65–70% has yet an antipsychotic effect whereas an occupancy of more than 80% raises the risk of EPS (Miyamoto, Duncan, Marx, & Lieberman, 2005).1 Besides this strong DA-D2 antagonism of most TA, each agent has individual effects on other neuronal receptors (DA-D1, a1, serotonergic (5-HT), histaminic, and muscarinic) leading to variable adverse effects (Miyamoto et al., 2005).1 The high frequency of adverse effects limits the use of the TA, especially at higher doses. Consequently, the use of TA in the treatment of tics cannot be recommended unconfined and other DARA with more tolerable risk of adverse effects should be considered as first-choice medication (Roessner et al., 2013). 3.1.1 Haloperidol Haloperidol was discovered by Paul Janssen in 1959 (Janssen et al., 19591; Lo´pez-Mun˜oz & Alamo, 20091) and quickly approved for treatment in Europe ( Jones, 2010).1 The clinical profile of action is characterized by its antipsychotic character. Furthermore, haloperidol has an antiemetic and a sedating effect, therapeutically appreciated in hyper- and dyskinetic disorders. In fact, the butyrophenone derivate was the first TA proved to be effective in the treatment of TS leading to tic reduction of 78–91% (Shapiro et al., 1989) but concerns about the adverse effects have limited its use since then (Singer, 2010).
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Nevertheless, some authors argue, that even if other TA (e.g., fluphenazine and pimozide) might have a slightly better tolerability, haloperidol remains a useful medication in the treatment of tics (Singer, 2010). In Germany, it is still the only approved agent for treating TS from the age of 3 (Roessner, 2012). The pharmacokinetics of haloperidol are described in Table 10.1.
3.1.1.1 Studies on the effectiveness of haloperidol in the treatment of TS
Haloperidol and pimozide were the first two agents proved to be effective in the treatment of tics in placebo-controlled trials (Roessner et al., 2013). There are several studies having assessed the effectiveness of haloperidol for the treatment of tics; three randomized, double-blind, placebocontrolled trials comparing haloperidol to pimozide (Ross & Moldofsky, 1978; Sallee, Nesbitt, Jackson, Sine, & Sethuraman, 1997; Shapiro et al., 1989), one double-blind, placebo-controlled study comparing haloperidol to trifluoperazine and tiospirone (Borison, Sinha, Haverstock, McLarnon, & Diamond, 1989), one naturalistic study comparing haloperidol to pimozide (Sandor, Musisi, Moldofsky, & Lang, 1990), and one retrospective chart review (Singer, Gammon, & Quaskey, 1985). Results of a randomized, double-blind, placebo-controlled crossover trials with a study period up to 20 months proved a significant tic reduction with both, pimozide and haloperidol (max. dose 12 mg) in nine patients (aged 8–28 years) with TS (Ross & Moldofsky, 1978). In another randomized, double-blind, placebo-controlled, study over 6 weeks, with both parallel-group and crossover design, including 57 patients (aged 18–65 years) at a maximum dose of 10 mg, the strong blockade of the DA-D2 receptors reduced tics in up to 80% of the cases and both, pimozide and haloperidol were more effective than placebo with a slight advantage of haloperidol over pimozide while haloperidol led to more adverse effects (Shapiro et al., 1989). In a 24-week, randomized, double-blind, placebo-controlled, doublecrossover study with 22 subjects (aged 7–16 years) using more commonly used doses of haloperidol (mean 3.5 mg) and pimozide (mean 3.4 mg), pimozide was found to be more effective than placebo in tic reduction, whereas haloperidol failed to have a significant effect, contrary to countless previous studies (Sallee et al., 1997). A long-term (up to 15 years) naturalistic study on 33 patients (aged 9–50 years) treated with pimozide (2–18 mg) or haloperidol (2–15 mg) found a comparable reduction of symptoms at follow-up, but more discontinuation
Table 10.1 Pharmacokinetic facts on typical and atypical antipsychotics used in the treatment of Tourette’s syndrome Agent
BA
Absorption
Peak plasma concentrations Protein binding
Haloperidol
High first pass effect, BA: 60–70% (Cheng et al., 1987; Forsman & Ohman, 1976; Holley, Magliozzi, Stanski, Lombrozo, & Hollister, 1983; Magliozzi & Hollister, 1985)
Fast, almost completely from GI tract Open Drug Database (ODDB)
OA: after 2–6 h, IMA: 20 min (Koninklijke, 2011)
90% (ODDB)
High lipophilia, 60% feces, 40% renally, only (whole body), Vd: 1% unchanged renally 7.9 2.5 l/kg (ODDB) (ODDB), therapeutic ranges assumed between 4 and 25 mg/l (Froemming, Lam, Jann, & Davis, 1989)
Pimozide
Significant firstpass metabolism by liver BA: 50%, OA (Sweetman, 2007)
Over gut and upper small intestines (ODDB)
After 3–8 h (Pinder et al., 1976)
a
a
Liver, oxidative 23–43 h N-dealkylation, elimination (Sweetman, 2007) mainly through urine in form of inactive metabolites (ODDB)
Fluphenazine
a
Absorbed from 2–5 h, after GI tract after oral application of intake (ODDB) 5 mg (ODDB)
Highly bound to plasma proteins (Baumann et al., 2004; Hiemke et al., 2011; Zhang & Bartlett, 2008)
Extremely high: 168–220 l/kg (Baumann et al., 2004; Hiemke et al., 2011; Zhang & Bartlett, 2008), High lipophilia: depot effect of 24 h (ODDB)
a
Distribution
Elimination
PEHL
Metabolism
24 h (12–38 h; OA) 21 h (13–36 h; IMA) (ODDB)
Completely in liver by glucuronization (CYP450 system) almost main way oxidative dealkylation (CYP3A4) (pharmacological inactive metabolites) (ODDB)
Mainly in liver by N-dealkylation (mediated by CYP3A4, to a lesser extent by CYP2D6), resulting in inactive metabolites (Sweetman, 2007)
1–2, 5 d (ODDB) Metabolized in liver and kidney (ODDB), Plasma concentration: about 0.5–500 ng/ml at steady state (Baumann et al., 2004; Hiemke et al., 2011; Zhang & Bartlett, 2008)
Risperidone
70–85% (Mannens et al., 1993)
Rapidly absorbed (Mannens et al., 1993)
After 1 h (Mannens et al., 1993)
77–89% (Leysen et al., 1988)
Steady state: 5 days (Leysen et al., 1988), Genetic influences such as CYP2D6 status (Huang et al., 1993), Weak relationship btw. daily dose and plasma concentration, but close to 9-OH-RSP (Aravagiri, Marder, Nuechterlein, & Gitlin, 2003)
Renal excretion with 9-OH-risperidone as the major compound and only 4% unchanged, Minor compound (14%) excreted by feces (Byerly & DeVane, 1996; Mauri et al., 2007) (ODDB)
Aripiprazole
87% (Winans, 2003)
Well resorbed (Mallikaarjun, Salazar, & Bramer, 2004)
After 3–5 h (OA) (Mallikaarjun et al., 2004)
Extensively bound to plasma proteins >99% (mainly albumin; DeLeon, Patel, & Crismon, 2004)
Steady state after 14 days (Mallikaarjun et al., 2004) Vd: 404 l (4.9 l/kg) (Mallikaarjun et al., 2004)
Kidney and liver excretion, 47–68 h (Mallikaarjun 25% recovered in urine (
Clinical Pharmacology of Dopamine-Modulating Agents in Tourette’s Syndrome Sabine Mogwitz, Judith Buse, Stefan Ehrlich, Veit Roessner1 Department of Child and Adolescent Psychiatry, University Medical Center, Technische Univerita¨t Dresden, Dresden, Germany 1 Corresponding author: e-mail address: [email protected]
Contents 1. Introduction 1.1 The role of dopamine in treatment of TS 2. DA Receptor Antagonists 2.1 Introduction 2.2 The mechanism of action 2.3 Adverse effects 2.4 Specific concerns during fertility stage 2.5 Interactions 2.6 Monitoring 3. Systematic Review of Dopamine Receptor Antagonists in the Treatment of TS 3.1 Typical antipsychotics 3.2 Atypical antipsychotics 3.3 Benzamides 4. Tetrabenazine 4.1 Studies on the effectiveness of tetrabenazine in the treatment of TS 4.2 Characteristic adverse effects of tetrabenazine 5. Dopamine Agonists 5.1 Studies on the effectiveness of dopamine agonists in the treatment of TS 5.2 Characteristic adverse effects of dopamine agonists 6. Summary References
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Abstract Forty years of research and clinical practice have proved dopamine (DA) receptor antagonists to be effective agents in the treatment of Tourette’s syndrome (TS), allowing a significant tic reduction of about 70%. Their main effect seems to be mediated by the blockade of the striatal DA-D2 receptors. Various typical and atypical agents are available and there is still discord between experts about which of them should be
International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00010-X
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2013 Elsevier Inc. All rights reserved.
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considered as first choice. In addition, there are suggestions to use DA receptor agonists such as pergolide or non-DA-modulating agents. The present chapter is focusing on the clinical pharmacology of DA-modulating agents in the treatment of TS. The introduction outlines their clinical relevance and touches on the hypotheses of the role of DA in the pathophysiology of TS. Subsequently, general information about the mechanisms of action and adverse effects are provided. The central part of the chapter forms a systematic review of all DA-modulating agents used in the treatment of TS, including an overview of studies on their effectiveness, and a critical discussion of their specific adverse effects. The present chapter closes with a summary of the body of evidence and a description of the resulting recommendations for the pharmacological treatment of TS.
1. INTRODUCTION Tics and tic-related behavioral symptoms can have a major impact on the patient’s performance at school and work and they can lead to social difficulties (Roessner et al., 2011). Quality of life was found to be significantly worse in patients with Tourette’s syndrome (TS) compared to healthy controls with tic severity being a usable predictor of quality of life (Cutler, Murphy, Gilmour, & Heyman, 2009). Individual treatment of a patient should be planned by considering the available diagnostic information, the level of the patient’s impairment, the effectiveness and tolerability of the treatment options, as well as the patient’s preference (Pringsheim et al., 2012; Roessner et al., 2011). If the benefit of behavioral therapy is not sufficient, pharmacotherapy should be added or should replace the previous treatment—always in combination with psychoeducation (Roessner et al., 2011). In severe cases with strong psychosocial impairment, poor coping or no availability of specialized behavioral therapy, initiation of pharmacological treatment might be considered right at the beginning (Roessner et al., 2011). Although pharmacotherapy of tics is the fastest and most promising treatment option (Roessner et al., 2011), pharmacological treatment is symptomatic, which means it improves the tics at best, but does not cure them (Gilbert, 2006). Additionally, there is no evidence yet that a short- to intermediate-term medication influences the natural long-term prognosis of tic symptoms, that is, there is no evidence that refraining from any treatment has negative consequences on the course of the disorder. Therefore, a watchful waiting does not necessarily imply having missed an important chance (Rothenberger & Roessner, 2013).
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Scientific evidence for the effectiveness of different pharmacological treatment options based on randomized, controlled trials is limited (Roessner et al., 2011). Especially studies meeting stringent methodological criteria and taking the effect of tic severity, comorbidities, and comedication into account are missing (Roessner, 2012). A particular difficulty in the evaluation of treatment options in TS is its waxing and waning course, that is, the fluctuation of frequency, intensity, location, and complexity of tics over time (Leckman, 2002). In addition to these “natural” changes of unknown cause over time, the modulating influence of environmental and/or psychosocial factors, such as stress, excitement, anxiety, anger, fatigue, concentration, and activity must be considered in order to judge the effectiveness of a certain treatment correctly (Roessner et al., 2011). Consequently, results of the two Cochrane reviews on pharmacological treatment of tics in TS (Curtis, Clarke, & Rickards, 2009; Pringsheim & Marras, 2009) concluded that the existing evidence for the effectiveness and safety of the studied drugs does not allow clear recommendations (Roessner et al., 2011). Long-term trials with larger groups of TS patients using the Yale Global Tic Severity Scale (YGTSS) as the primary outcome measure and standardized rating scales to assess adverse effects such as the Extrapyramidal Symptom Rating Scale are needed. Nevertheless, 30 years of experience with treatment of TS have established a number of pharmacological agents as promising first-line treatment for TS. However, the huge variety of substances used indicates that none of them is ideal, and none of them provides complete relief without adverse effects in all patients (Roessner et al., 2011).
1.1. The role of dopamine in treatment of TS Almost since the beginning of research on TS, tics have been associated with a dysfunction of the dopamine (DA) system. For a long time this assumption was mainly based on clinical findings of DA receptor antagonists (DARA) being the most effective drugs in treating tics with a marked decrease of tics in about 70% of cases (Shapiro & Shapiro, 1998). In recent years, nuclear imaging has allowed a much deeper understanding of DA neurotransmission. Based on the findings of various positron emission tomography (PET) and single-photon emission computer tomography (SPECT) studies, four hypotheses on DA dysfunction in TS are discussed: (1) DA hyperinnervation, (2) supersensitive DA receptors, (3) presynaptic DA abnormality, and (4) DA tonic–phasic dysfunction (Buse, Schoenefeld, Mu¨nchau, & Roessner, 2013; Singer, 2013).
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Beside the apparent evidence for deviances in the DA system, suggestions concerning imbalances in other neurotransmission systems like the serotonergic, the noradrenergic, the glutamatergic, the GABAergic, the cholinergic, and the opioid system have been made (Harris & Singer, 2006; Swain, Scahill, Lombroso, King, & Leckman, 2007).
2. DA RECEPTOR ANTAGONISTS 2.1. Introduction “DA receptor antagonism” describes a pharmacodynamics feature of various agents used for numerous indications. In fact, all antipsychotics show some DA receptor antagonism (Patteet et al., 2012).1 A distinction is made between agents designed before the 1980s, called first-generation antipsychotics and the drugs designed more recently, defined as second-generation antipsychotics. Since the latter are assumed to cause less extrapyramidal motor symptoms (EPS) they are called atypical antipsychotics (AA) compared to the first-generation antipsychotics which are considered to cause “typical” adverse effects and are therefore called typical antipsychotics (TA). But in fact, the differentiation between the TA and AA is not always that clear (Almandil & Wong, 20111; Moleman, 20091). Since their introduction in the 1950s antipsychotics are mostly used to treat schizophrenia and schizoaffective disorders (Patteet et al., 2012).1 But since 40 years studies of different quality have proved antipsychotics to be also effective in reducing tics to a significant degree (Mu¨ller-Vahl, 2007; Shapiro & Shapiro, 1998; Silay & Jankovic, 2005; Singer, 2000). Recent reviews and guidelines on pharmacological treatment of TS recognized DARA as the most effective pharmacological treatment for tics (Roessner et al., 2011, 2013; Weisman, Qureshi, Leckman, Scahill, & Bloch, 2012), but also alpha-2 agonists including clonidine and ganfacine are often stated as the first-line pharmacological treatment, because of their more benign safety profile (Pringsheim et al., 2012). However, recommendation of the latter ones is questioned by recent meta-analytic findings that the modest but significant benefit of alpha-2 agonists in the treatment of children with TS is mainly moderated by its impact on comorbid attention deficit hyperactivity disorder (ADHD) and that in the absence of ADHD,
1
Publications not primarily focusing on tics and/or Tourette’s Syndrome (TS) (publications on tics and/or TS are not marked).
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however, the efficacy of these agents was small and nonsignificant (Weisman et al., 2012). Overall, there is still discord between experts about the first-choice agent due to the deficient body of evidence, regional differences, and personal experience (Roessner et al., 2011). Due to the fluctuating symptomatology only with the help of double-blind, placebo-controlled studies of longer duration, a sufficient statement about the efficacy of agents in the treatment of TS can be made (Mu¨ller-Vahl, 2007).
2.2. The mechanism of action Antipsychotics influence the synaptic gateways in the brain by influencing the transfer of DA. The mechanism on which they act is DA receptor antagonism (Patteet et al., 2012).1 In fact, all antipsychotics block the consequences of the probably inappropriate presynaptic DA release (Howes & Kapur, 2009).1 TA show higher affinity for DA-D2 receptors than for DA-D1 receptors. AA, like sulpiride, can be highly selective for DA-D2 receptors, but others, like clozapine, are relatively nonselective for both DA-D1 and DA-D2 and highly selective for DA-D4 receptors (Rang, Dale, Ritter, & Moore, 2003).1 It can be stated: the stronger the potency of the DA blockade, the more effective is a drug in reducing psychotic syndromes as well as tics (Scahill et al., 2006). However, a strong blockade of DA receptors also correlates with the frequency of adverse effects, such as EPS (Bressan, Jones, & Pilowsky, 2004).1 Additionally, antipsychotics can also interact with receptors for serotonin, acetylcholine, histamine, and noradrenaline (norepinephrine) and thereby alter cholinergic, serotonergic, histaminergic, and alpha-adrenergic transmission (Roessner et al., 2013).
2.3. Adverse effects The use of antipsychotic agents seems to be a difficult trade-off between the benefit of reducing symptoms and the risk of troubling, sometimes even lifeshortening adverse effects (Muench & Hamer, 20101; Pringsheim et al., 2012). General adverse effects of antipsychotics due to their affinity to DA receptors are extrapyramidal motor symptoms (EPS) including Parkinsonlike symptoms such as tremor, akinesia, rigidity, and rabbit syndrome (a rare form of EPS characterized by involuntary, rhythmic motions of the mouth) but also dystonia, dyskinesia, and akathisia (Muench & Hamer, 2010).1
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Tardive dyskinesia (TD) is a serious and potentially irreversible adverse effect that can occur after longer treatment with antipsychotics. Several single case studies reported about TD in patients with TS (Golden, 1985; Riddle, Hardin, Towbin, Leckman, & Cohen, 1987; Silva, Magee, & Friedhoff, 1993), but a recent review raised doubts about the occurence of this severe side effect in patients with TS. Out of 521 patients treated with antipsychotics none ever developed TD. The rate of TD was significantly reduced compared to other psychiatric populations which led the authors to the assumption that TS might even prevent TD (Mu¨ller-Vahl & Krueger, 2011). In a review on motor side effects of antipsychotic use in children and adolescent, the prevalence rate of TD was found to be 1–5%, which is rather low compared to about 20% in adults (Wolf & Wagner, 1993).1 However, more often than TD, anxious/depressed symptoms such as shyness, lack of lust, avoiding school, and social withdrawal occur under treatment with haloperidol or pimozide (Linet, 1985; Mikkelsen, Detlor, & Cohen, 1981). Another common endocrine effect due to DA receptor antagonism is an increase of prolactin concentration associated with amenorrhea, erectile dysfunction (Muench & Hamer, 2010),1 infertility, and decreased libido (Freedman, 20031; Moleman, 20091; Sitsen, Cohen, & Franson, 20091). A rare but life-threatening complication is the neuroleptic malignant syndrome (NMS), characterized by muscle rigidity, rapid rise in body temperature, and mental confusion. It usually occurs with initiation of therapy or with dose adjustment. Incidence rates range from 0.02% to 3% among patients taking antipsychotics, whereas the risk is highest under treatment with TA. Death by renal or cardiac failure as a consequence of the NMS occurs in 10–20% (Levenson, 19851; Velamoor, 19981). Some antipsychotics cause a prolongation of the cardiac QT interval associated with an increased risk for “torsade de pointes” tachycardia, tachyarrhythmia, tachycardia, and sudden cardiac death (Blair, Scahill, State, & Martin, 20051; Glassman & Bigger, 20011; Muench & Hamer, 20101; Zareba & Lin, 20031). The greatest change in QT interval was seen under treatment with thioridazine (Glassman & Bigger, 2001).1 However, changes of the QT interval are often only relevant at toxic doses. The greatest risk is seen in women and elderly patients (Letsas et al., 2006) as well as in patients with concomitant cardiovascular pathologies, electrolyte imbalance (hypopotassemia and hypomagnesemia), hepatic or renal dysfunction, and coadministration of other drugs known to change the QT interval
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Figure 10.1 Overview of adverse effects caused by TA and AA in patients with tics. Halo, haloperidol; Ola, olanzapine; Clo, clozapine; Ris, risperidone; AA, atypical antipsychotics; TA, typical antipsychotics; Que, quetiapine; Ari, aripiprazole; Zip, ziprasidone.
(Moleman, 20091; Rettenbacher et al., 20051; Rizzo, Gulisano, Calı`, & Di Pino, 2013; Van Noord et al., 20091). Figure 10.1 shows common adverse effects of TA and AA and the agents causing them most frequently. 2.3.1 Adverse effects due to the affinity on serotonin receptors Blocking serotonin receptors can result in increased appetite and weight gain (Mathews & Muzina, 2007).1 2.3.2 Adverse effects due to the affinity on muscarinic acetylcholine receptors Blocking muscarinic acetylcholine receptors may lead to typical anticholinergic effects like blurred vision, increased ocular pressure, dry mouth and eyes, constipation, and urinary retention (Patteet et al., 2012).1
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2.3.3 Adverse effects due to the affinity on histamine-H1 receptors Drugs blocking histamine-H1 receptors are generally associated with weight gain (Czobor et al., 20021; Kroeze et al., 20031) or sedation (Patteet et al., 2012).1 Metabolic consequences, which might also occur without associated marked weight gain, include increased triglycerides, cholesterol, and glucose (Meyer, 2002)1; diabetes mellitus type 2 (Roessner et al., 2007); and secondary cardiovascular complications. Also, the possibility of an asymptomatic hypoglycemia during treatment has to be considered indicating a global disturbance of glucose metabolism (Budman, Gayer, Lesser, Shi, & Bruun, 2001). Given the potential metabolic side effects, regular controls of body weight, blood sugar levels, and serum lipids are recommended. 2.3.4 Adverse effects due to the affinity on a-adrenergic receptors Blocking a-adrenergic receptors can result in orthostatic hypotension (Patteet et al., 2012),1 sexual side effects, and nasal congestion (Mathews & Muzina, 2007).1
2.4. Specific concerns during fertility stage Beside decreased libido, a common adverse effect of TA and some AA, such as amisulpride and risperidone, is raised prolactin levels with the consequence of disturbances in menstrual cycle, gynecomastia, and galactorrhea. Although ethical reasons forbid studies with pregnant women, today systematically gathered knowledge on possible risks during pregnancy is available. Risperidone and quetiapine should be preferred during pregnancy due to their good tolerability and the number of documented uncomplicated pregnancies (Gentile, 20101; Reis & Ka¨lle´n, 20081; Rohde, Dorsch, & Schaefer, 20121). There are also several hundred reports about pregnancies under treatment with clozapine und olanzapine, but the associated hematologic and metabolic risks are critically discussed (Rohde et al., 2012).1 There are no signs for risk for the (unborn) child under treatment with amisulpride and ziprasidone either, but research data are scarce (Gentile, 20101; Reis & Ka¨lle´n, 20081). Due to warning results from animal studies, treatment in pregnant patients should not be initiated with aripiprazole but in cases a treatment with aripiprazole is already established a change of the agent with pregnancy onset is not always indicated (Gentile, 20101; Rohde et al., 20121). If antipsychotic treatment is administered until delivery, the newborn might exhibit transient adaptation problems like agitation, sedation, or drinking
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problems. Also, EPS might be observed in the newborn, especially if the mother has been treated with TA (Rohde et al., 2012).1 Since active substances of antipsychotics pass into breast milk, the common safety advice is that women treated with DARA should not breast feed. However, it is discussed as well whether the benefits of breastfeeding might outweigh the risks of exposing the babies to very low amounts of antipsychotic drugs (Te´nyi, Csa´bi, & Trixler, 2000).1
2.5. Interactions In clinical psychiatric practice comedication is often necessary, for example, in patients with comorbid psychiatric disorders or somatic diseases. Pharmacokinetic interactions can be observed if absorption, distribution, metabolism, or excretion of one drug is influenced by another. If two drugs interact at the same binding sites this might lead to additive, synergistic, or antagonistic effects. Most interactions with antipsychotics are associated with their metabolism, which is mediated by cytochrome P (CYP) enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) or uridine diphosphate glucuronosyltransferases (Spina & de Leon, 2007). Active metabolites, produced during elimination of antipsychotic agents can also inhibit CYP enzymes (Murray, 20061; Spina & de Leon, 2007). Selective serotonin reuptake inhibitor (SSRI) are able to cause a relevant inhibition of CYP enzymes (Spina & de Leon, 2007; Wille, Cooreman, Neels, & Lambert, 20081). Concomitant use of antipsychotics and dopaminergic medication, such as antiparkinsonism drugs and prolactin inhibitors, is not recommended because of their opposing effects (Patteet et al., 2012).1 Most antipsychotics can enhance central effects of other agents like central nervous system (CNS)-depressant drugs, antihypertensive drugs, and alcohol (Sweetman, 2007).1 The effect of antipsychotics can also be potentially reduced through co-consumation of coffee, black tea, some fruit juices, milk, antacid drugs, smoking (induction of enzymes), and anticonvulsants.
2.6. Monitoring A systematic anamnesis of the patient and a standardized assessment of the tic symptoms, for example, with the YGTSS are obligate. The clinical and neurological status prior to the first drug administration should be assessed to rule out existing contraindications for applying the chosen medication (Cath et al., 2011). Regular blood work is needed, especially blood sugar, liver and kidney parameters, blood cells due to the risk of low leukocytes, hyperglycemia, hypercholesteremia, hyperlipidemia, and hyperprolactinemia.
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An ECG to detect possible changes of the cardiac QT interval (risk of reentry tachycardia) should be conducted at least annually and is mandatory before starting the treatment (Rizzo et al., 2013; Roessner et al., 2011).
3. SYSTEMATIC REVIEW OF DOPAMINE RECEPTOR ANTAGONISTS IN THE TREATMENT OF TS 3.1. Typical antipsychotics TA are mainly used in the treatment of schizophrenia, because of their antipsychotic effect on positive symptoms (Patteet et al., 2012),1 but are also effective in the treatment of TS (Shapiro et al., 1989). Their effect is mainly due to a strong antagonism of DA-D2 receptors. The DA receptor occupancy is correlated with the antipsychotic potency but must also be seen as a predictor of adverse effects: a striatal DA-D2 occupancy of 65–70% has yet an antipsychotic effect whereas an occupancy of more than 80% raises the risk of EPS (Miyamoto, Duncan, Marx, & Lieberman, 2005).1 Besides this strong DA-D2 antagonism of most TA, each agent has individual effects on other neuronal receptors (DA-D1, a1, serotonergic (5-HT), histaminic, and muscarinic) leading to variable adverse effects (Miyamoto et al., 2005).1 The high frequency of adverse effects limits the use of the TA, especially at higher doses. Consequently, the use of TA in the treatment of tics cannot be recommended unconfined and other DARA with more tolerable risk of adverse effects should be considered as first-choice medication (Roessner et al., 2013). 3.1.1 Haloperidol Haloperidol was discovered by Paul Janssen in 1959 (Janssen et al., 19591; Lo´pez-Mun˜oz & Alamo, 20091) and quickly approved for treatment in Europe ( Jones, 2010).1 The clinical profile of action is characterized by its antipsychotic character. Furthermore, haloperidol has an antiemetic and a sedating effect, therapeutically appreciated in hyper- and dyskinetic disorders. In fact, the butyrophenone derivate was the first TA proved to be effective in the treatment of TS leading to tic reduction of 78–91% (Shapiro et al., 1989) but concerns about the adverse effects have limited its use since then (Singer, 2010).
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Nevertheless, some authors argue, that even if other TA (e.g., fluphenazine and pimozide) might have a slightly better tolerability, haloperidol remains a useful medication in the treatment of tics (Singer, 2010). In Germany, it is still the only approved agent for treating TS from the age of 3 (Roessner, 2012). The pharmacokinetics of haloperidol are described in Table 10.1.
3.1.1.1 Studies on the effectiveness of haloperidol in the treatment of TS
Haloperidol and pimozide were the first two agents proved to be effective in the treatment of tics in placebo-controlled trials (Roessner et al., 2013). There are several studies having assessed the effectiveness of haloperidol for the treatment of tics; three randomized, double-blind, placebocontrolled trials comparing haloperidol to pimozide (Ross & Moldofsky, 1978; Sallee, Nesbitt, Jackson, Sine, & Sethuraman, 1997; Shapiro et al., 1989), one double-blind, placebo-controlled study comparing haloperidol to trifluoperazine and tiospirone (Borison, Sinha, Haverstock, McLarnon, & Diamond, 1989), one naturalistic study comparing haloperidol to pimozide (Sandor, Musisi, Moldofsky, & Lang, 1990), and one retrospective chart review (Singer, Gammon, & Quaskey, 1985). Results of a randomized, double-blind, placebo-controlled crossover trials with a study period up to 20 months proved a significant tic reduction with both, pimozide and haloperidol (max. dose 12 mg) in nine patients (aged 8–28 years) with TS (Ross & Moldofsky, 1978). In another randomized, double-blind, placebo-controlled, study over 6 weeks, with both parallel-group and crossover design, including 57 patients (aged 18–65 years) at a maximum dose of 10 mg, the strong blockade of the DA-D2 receptors reduced tics in up to 80% of the cases and both, pimozide and haloperidol were more effective than placebo with a slight advantage of haloperidol over pimozide while haloperidol led to more adverse effects (Shapiro et al., 1989). In a 24-week, randomized, double-blind, placebo-controlled, doublecrossover study with 22 subjects (aged 7–16 years) using more commonly used doses of haloperidol (mean 3.5 mg) and pimozide (mean 3.4 mg), pimozide was found to be more effective than placebo in tic reduction, whereas haloperidol failed to have a significant effect, contrary to countless previous studies (Sallee et al., 1997). A long-term (up to 15 years) naturalistic study on 33 patients (aged 9–50 years) treated with pimozide (2–18 mg) or haloperidol (2–15 mg) found a comparable reduction of symptoms at follow-up, but more discontinuation
Table 10.1 Pharmacokinetic facts on typical and atypical antipsychotics used in the treatment of Tourette’s syndrome Agent
BA
Absorption
Peak plasma concentrations Protein binding
Haloperidol
High first pass effect, BA: 60–70% (Cheng et al., 1987; Forsman & Ohman, 1976; Holley, Magliozzi, Stanski, Lombrozo, & Hollister, 1983; Magliozzi & Hollister, 1985)
Fast, almost completely from GI tract Open Drug Database (ODDB)
OA: after 2–6 h, IMA: 20 min (Koninklijke, 2011)
90% (ODDB)
High lipophilia, 60% feces, 40% renally, only (whole body), Vd: 1% unchanged renally 7.9 2.5 l/kg (ODDB) (ODDB), therapeutic ranges assumed between 4 and 25 mg/l (Froemming, Lam, Jann, & Davis, 1989)
Pimozide
Significant firstpass metabolism by liver BA: 50%, OA (Sweetman, 2007)
Over gut and upper small intestines (ODDB)
After 3–8 h (Pinder et al., 1976)
a
a
Liver, oxidative 23–43 h N-dealkylation, elimination (Sweetman, 2007) mainly through urine in form of inactive metabolites (ODDB)
Fluphenazine
a
Absorbed from 2–5 h, after GI tract after oral application of intake (ODDB) 5 mg (ODDB)
Highly bound to plasma proteins (Baumann et al., 2004; Hiemke et al., 2011; Zhang & Bartlett, 2008)
Extremely high: 168–220 l/kg (Baumann et al., 2004; Hiemke et al., 2011; Zhang & Bartlett, 2008), High lipophilia: depot effect of 24 h (ODDB)
a
Distribution
Elimination
PEHL
Metabolism
24 h (12–38 h; OA) 21 h (13–36 h; IMA) (ODDB)
Completely in liver by glucuronization (CYP450 system) almost main way oxidative dealkylation (CYP3A4) (pharmacological inactive metabolites) (ODDB)
Mainly in liver by N-dealkylation (mediated by CYP3A4, to a lesser extent by CYP2D6), resulting in inactive metabolites (Sweetman, 2007)
1–2, 5 d (ODDB) Metabolized in liver and kidney (ODDB), Plasma concentration: about 0.5–500 ng/ml at steady state (Baumann et al., 2004; Hiemke et al., 2011; Zhang & Bartlett, 2008)
Risperidone
70–85% (Mannens et al., 1993)
Rapidly absorbed (Mannens et al., 1993)
After 1 h (Mannens et al., 1993)
77–89% (Leysen et al., 1988)
Steady state: 5 days (Leysen et al., 1988), Genetic influences such as CYP2D6 status (Huang et al., 1993), Weak relationship btw. daily dose and plasma concentration, but close to 9-OH-RSP (Aravagiri, Marder, Nuechterlein, & Gitlin, 2003)
Renal excretion with 9-OH-risperidone as the major compound and only 4% unchanged, Minor compound (14%) excreted by feces (Byerly & DeVane, 1996; Mauri et al., 2007) (ODDB)
Aripiprazole
87% (Winans, 2003)
Well resorbed (Mallikaarjun, Salazar, & Bramer, 2004)
After 3–5 h (OA) (Mallikaarjun et al., 2004)
Extensively bound to plasma proteins >99% (mainly albumin; DeLeon, Patel, & Crismon, 2004)
Steady state after 14 days (Mallikaarjun et al., 2004) Vd: 404 l (4.9 l/kg) (Mallikaarjun et al., 2004)
Kidney and liver excretion, 47–68 h (Mallikaarjun 25% recovered in urine (
