Classics in Chemical Neuroscience: Risperidone - ACS Publications

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Classics in Chemical Neuroscience: Risperidone Trevor C Chopko, and Craig W Lindsley ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00159 • Publication Date (Web): 25 Apr 2018 Downloaded from http://pubs.acs.org on April 29, 2018

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ACS Chemical Neuroscience

Classics in Chemical Neuroscience: Risperidone Trevor C. Chopko1 and Craig W. Lindsley1,2,3

1

Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States

2

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States

3

Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States

Abstract

After identifying the influence of serotonergic receptors in ameliorating the negative symptoms associated with schizophrenia, atypical antipsychotics were developed incorporating dopamine and serotonin antagonism. Risperidone, sold under the trade name Risperdal, was the second atypical antipsychotic developed following clozapine, but quickly became a first-line treatment for acute and chronic schizophrenia due to its preferential side effect profile. Despite initial FDA-approval 25 years ago, risperidone continues to be a fundamental treatment in schizophrenia, bipolar I disorder, and autism-related irritability. It is on the World Health Organization’s List of Essential Medicines for its balance of efficacy, safety, tolerability, and cost-effectiveness. In this review, we highlight the history and importance of risperidone as an atypical antipsychotic, in addition to its chemical synthesis, manufacturing, drug metabolism and pharmacokinetics, pharmacology, structure-activity relationship, indications, and adverse effects. Keywords: Risperidone, Risperdal, schizophrenia, atypical, dopamine, serotonin, adrenergic, histamine, D2, 5-HT2A Background Schizophrenia is a debilitating mental disorder affecting 1% of the world’s population that is associated with positive (delusions, hallucinations, disorganized speech, abnormal psychomotor behavior) and negative symptoms (diminished emotional expression, avolition, catatonia, anhedonia), in addition to cognitive impairments in executive function and working memory.1-2 The symptoms and severity of the disease are highly variable between patients and often arise progressively or abruptly in cycles of remissions or relapse. Schizophrenia not only affects the health and well-being of the patients, but also 1 ACS Paragon Plus Environment

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carries an immense economic impact on the patients and society resulting from institutionalization and chronic treatments.3 The World Health Organization (WHO) estimated in 2004 that the mental disorder ranked fifth in males and sixth in females as the leading cause of total years lost due to the disability, a measure of healthy life lost in less than healthy states.4 Patients with schizophrenia have decreased rates of employment, developing close relationships/marrying, and independent living, while increased rates of substance abuse, depression, suicide, homelessness, morbidity, and mortality.3,5-9 Although the exact pathophysiology underlying schizophrenia remains unresolved, amphetamine- and lysergic acid diethylamide (LSD)-induced animal models have highlighted the impact of overactive dopamine and serotonin receptors in the production of positive (dopamine) and negative (serotonin) symptomalogy.1011 The first-line therapy in treating schizophrenia involves atypical antipsychotics (risperidone, olanzapine, paliperidone, ziprasidone, aripiprazole quetiapine), with clozapine reserved for treatmentresistant patients (Figure 1).12-13 Bipolar disorder is a mental illness that affects over 1% of the global population and is characterized by episodic fluctuations of mood into depression or elation. It is a major cause of disability resulting in cognitive and functional impairments, as well as increased risk of mortality, often by suicide.14 The disorder is divided into two distinct categories: bipolar I disorder defined by mania and bipolar II disorder defined by major depression and hypomania.15 The pathology of bipolar disorder is not fully elucidated, but pharmacological models indicate that overactive dopaminergic signaling plays a role in mania, whereas the contrary underlies depression.16 The first-line treatment for bipolar I disorder includes either lithium or valproate plus an antipsychotic, with atypical antipsychotics (olanzapine and risperidone) preferred over typical antipsychotics. Lithium and valproate function by mitigating downstream pathways activated by dopamine receptors to modulate dopaminergic activity.17 In bipolar II disorder, the first-line treatment is lithium or lamotrigine, with antidepressants reserved for severely ill patients.18 Autism spectrum disorder (ASD) develops in early childhood and is marked by impairments in social, speech, and behavioral skills as well as restricted and/or repetitive behaviors.19 ASD is comprised of autistic disorder, Asperger’s syndrome, and atypical autism and people with ASD often also have other developmental issues, such as mental retardation, learning difficulties, attention deficit hyperactivity disorder, and Tourette’s syndrome.20 Prior to 1990, the prevalence of autism was reported to be 3 in 1,000 children, but has since increased to an estimated 1 in 68 children in 2010.21-22 Autism is challenging to treat because it does not have a clear, generalizable biochemical underpinning and has been shown to be related to numerous genetic and environmental factors.23 Currently, there are only two FDA-approved drugs for the treatment of autism in risperidone and aripiprazole (4). While both target irritability or behavioral issues, neither improves the fundamental deficits in social skills and behavioral repetition.24 Typical, or first-generation, antipsychotics primarily elicit efficacy on the positive symptoms by antagonizing D2 receptors, but often produced undesired extrapyramidal side effects (EPS; tremors, spasms, rigidity, tardive dyskinesia) and hyperprolactinemia.25-27 EPS result from antagonism at nigrostriatal D2 receptors, while hyperprolactinemia is caused by modulation at tuberoinfundibular D2 receptors.28 Atypical antipsychotics predominantly exhibit therapeutic efficacy from their blockade at 2 ACS Paragon Plus Environment

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cortical serotonin receptors and limbic dopamine receptors. While atypical antipsychotics do not entirely eliminate the risks of EPS and hyperprolactinemia, the incidence is dramatically reduced when administered in clinically effective ranges.29 Atypical antipsychotics elude these incapacitating side effects by transiently occupying the D2 receptors and rapidly dissociating to allow for normal dopamine neurotransmission.30 The balance between the serotonin-dopamine blockage associated with atypicality is efficacious in treating numerous mental illnesses with improved tolerability and safety profile compared to typical antipsychotics.31-32

Figure 1. Chemical Structures of Common D2 and/or 5-HT2A Antagonists.

Risperidone is a potent atypical antipsychotic with antagonist binding affinity at serotoninergic, dopaminergic, adrenergic, and histaminergic receptors, lacking any affinity for muscarinic receptors.33 It is currently FDA-approved in the treatment of acute and chronic schizophrenia, bipolar I disorder (monotherapy or adjunctive therapy), and irritability associated with autistic disorder in children, adolescents, adults, and the elderly.34 It is also effectively used in schizoaffective disorder, depression with psychosis, and psychosis secondary to general medical conditions. Though research is still ongoing, risperidone may be effective in other conditions including major depressive disorder, obsessive compulsive disorder, delirium, dementia, and substance abuse.35-37 The active metabolite of risperidone, 9-hydroxyrisperidone or paliperidone, is marketed under the trade name Invega and FDA-approved for schizophrenia and schizoaffective disorder (monotherapy or adjunctive therapy).38 The aim of this review is to showcase and elucidate the history and importance of risperidone in the treatment of CNS disorders, in addition to highlighting its chemical synthesis, manufacturing, drug metabolism and pharmacokinetics, pharmacology, structure-activity relationship, indications, and adverse effects. Chemical Properties and Synthesis Risperidone is sold under the trade name Risperdal, among other common names as Psychodal, Apexidone, and R 64766 (Janssen).39 It carries the IUPAC name 3-(2-(4-(6-fluorobenzo[d]isoxazol-3yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CAS no. 1062663 ACS Paragon Plus Environment


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06-2) and features a 3-fluoro-1,2-benzisoxazole para-attached to a piperidine central core that is Nethyl-linked to a 6,7,8,9-tetrahydro-2-methyl-pyridopyrimidin-4-one. It has a molecular formula of C23H27FN4O2, molecular weight of 410.493 g/mol, melting point of 170 °C, and topological surface area of 61.9 Å. Two ionization constants exist for risperidone, pKa1=8.24 and pKa2=3.11, and the molecule has a partition coefficient of 3.49.39-42 This achiral small molecule contains four rotatable bonds with zero hydrogen bond donors and four hydrogen bond acceptors.39 Risperidone’s properties comply with all of Lipinski’s and Veber’s rules, and its lipophilicity contributes to its ability to cross the blood-brain barrier (BBB). The original synthesis of risperidone is detailed in Schemes 1 and 2.43-44 It begins with the chlorination of 11-acetylpiperidine-4-carboxlic acid (8) using thionyl chloride to generate 1-acetylpiperidine-4-carbonyl chloride (9). Utilizing a Friedel-Crafts acylation with 1,3-difluorobenzene afforded intermediate 10, which undergoes hydrolysis under acidic reflux conditions to form (2,4-difluorophenyl)(piperidin-4-yl) methanone hydrochloride (11). After the addition of hydroxylamine hydrochloride to 11, the subsequent oxime (mixture of syn- and anti-oximes) were formed.44 Cyclization of the syn-oxime occurs by refluxing in potassium hydroxide and water (1:1) to afford 6-fluoro-3-(piperidin-4-yl)-1,2benzisoxazole (13). Scheme 1. Synthesis of 6-fluoro-3-(piperidin-4-yl)-1,2-benzisoxazole.

2-Aminopyridine (14) is condensed with 3-acetyldihydrofuran-2(3H)-one (15) through a bimolecular cycloaddition reaction to produce intermediate 16. A hydrogenation is performed utilizing palladium on carbon, followed by formation of the primary halide to provide 3-(2-chloroethyl)-2-methyl-6,7,8,9tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (18). Risperidone (1) is formed through an SN2 reaction of 13 and 18 with potassium carbonate and potassium iodide in DMF.44 Numerous variations and optimizations on this synthetic route exist for risperidone and its analogues, often involving alterations to the order of steps or combining reactions to reduce the number of steps.45 Nadkarni and Shah improved the cyclization of the cis/trans oximes (12) with the substituted halopyrimidinone (18) by refluxing the reaction mixture for 4-10 hours, followed by the addition of base when cooled and then maintaining the reaction at room temperature for 10-18 hours.46 Avoidance of 4 ACS Paragon Plus Environment

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DMF, a solvent harmful to human health and difficult to remove from the final product due to its high boiling point, can be achieved through the synthesis depicted in Scheme 3. 2-Aminopyridine (14) is

Scheme 2. Synthesis of Risperidone.

condensed with methyl acetoacetate and p-toluene sulfonic acid to form the pyridopyrimidinone intermediate (19). After reduction to intermediate 20, bromination afforded compound 21. A Stille reaction with tributyl (vinyl)stannane and tetrakis(triphenylphosphine)-palladium catalyst yields the vinyl derivative (22). Subsequent hydroboration followed by oxidation of the resulting primary alcohol provides the aldehyde (23). A reductive amination with intermediate 23 and 6-fluoro-3-(piperidin-4-yl)1,2-benzisoxazole (13) yields risperidone (1), utilizing easily removable, volatile solvents throughout.47 Scheme 3. Alternative Synthesis of Risperidone.

Manufacturing Information

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Janssen Pharmaceuticals received FDA approval to market the treatment of risperidone for schizophrenia in 1993, short-term treatment of acute manic or mixed episodes associated with bipolar I disorder in 2003, and autism-related irritability in 2006.35 Risperidone was launched in January 1994 under the trade name Risperdal in 0.25 mg, 0.50 mg, 1 mg, 2 mg, 3 mg, and 4 mg white/slightly beige tablets, as well as a 1 mg/mL oral solution.33 Inactive ingredients in the tablets are colloidal silicon dioxide, hydroxypropyl methylcellulose, propylene glycol, sodium laurel sulfate, and corn starch. Inactive ingredients in the oral solution include tartaric acid, benzoic acid, sodium hydroxide, and purified water.48 Janssen Pharmaceuticals also introduced Risperdal Consta in 2003 and became the first long-acting injectable atypical antipsychotic.33 The original patent for risperidone expired in 2013 and numerous generic manufacturers (Ajanta Pharma Ltd., Apotex Inc., Aurobindo Pharma, Cipla, Dr. Reddy’s Laboratories Ltd., Mylan, Oxford Pharmaceuticals, Pliva Hrvatska d.o.o., Prinston Pharmaceutical Inc., Sandoz, Sun Pharmaceutical Industries Ltd., Teva Pharmaceutical Industries, Torrent Pharmaceuticals, Wockhardt, and Zydus Pharmaceuticals USA Inc.) have received FDA approval for the 0.25–4 mg quantities in tablet and oral administration.40 Janssen Pharmaceuticals received FDA approval for an extended-release tablet of risperidone’s active metabolite, paliperidone or 9-hydroxyrisperidone (24), which is marketed under the trade name Invega.33 A long-acting injectable palmitoyl ester of paliperidone was also introduced as Invega Sustenna (once every 28 days) and Invega Trinza (four injections annually).49-50 Based on 2011-2012 revenue reports, Risperdal Consta, Invega Sustenna, and Invega ranked as the seventh, eighth, and ninth top antipsychotics in the United States, earning $498 million, $473.6 million, and $401.7 million, respectively.51 Drug Metabolism and Pharmacokinetics Following oral administration, risperidone is almost entirely absorbed in the gastrointestinal (GI) tract with only 1% of the dose being recovered in the feces as the unchanged drug.28,34 The absolute bioavailability (F) of risperidone is 70% and the relative oral bioavailability from a tablet is 94% when compared with a solution. Plasma protein binding of risperidone is 90% and its active metabolite, 9hydroxy-risperidone (24), is 77%.44 9-Hydroxy-risperidone is considered to be equipotent to the parent drug and is marketed as Invega.38,52 Its ability to hydrogen bond decreases lipophilicity and consequently its diffusion through the BBB. The free-fraction of risperidone is 10 ng/mL and 9-hydroxy-risperidone is 50 ng/mL.53 The plasma half-life (t1/2) of risperidone is 3 h in extensive metabolizers and 20 h in poor metabolizers, which contrasts with the half-life of 24 of 21 h in extensive metabolizers and 30 h in poor metabolizers.54 Food administration does appear to influence the pharmacokinetics substantially and alcohol is not advised.34 Clearance values for risperidone and the active metabolite are estimated to be 4.6 and 6 L/h, respectively.55 The active metabolite is removed largely through renal excretion, while 80% of total clearance of the unchanged drug occurs via non-renal excretion.44 Metabolic biotransformation is the primary route of elimination of risperidone, with varying intrinsic clearance values between polymorphisms. Cytochrome P450 (CYP450) enzymes in the liver are largely responsible for the metabolism of risperidone. CYP2D6 is predominantly responsible for hydroxylation to 24, although CYP3A4 is involved to a lesser extent.56-57 Given the CYP genetic polymorphisms in a population, variance in PK parameters occur between extensive and poor metabolizers. Current evidence does not suggest CYP genotyping prior to the administration of risperidone, but it should not 6 ACS Paragon Plus Environment

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be excluded as an asset for treatment and dose optimization. Due to limitations in the sample size of most studies, conflicting answers have been reported on whether patients may elude potential adverse effects through genotyping.58-59 Regarding the PK difference between genotypic species, steady-state concentrations are achieved in one day with extensive metabolizers and five days in poor metabolizers. Peak concentrations (Cmax) of the active metabolite occur at 3 h in extensive metabolizers and 13 h in poor metabolizers.60 The predominant metabolic pathways, including N-dealkylation and hydroxylation, are depicted in Figure 2.

Figure 2. Metabolic Biotransformation Pathways of Risperidone.44 Drug-drug interactions occur with concomitant administration of CYP2D6 inhibitors and lead to an increased plasma concentration of the active moiety, which is the sum of activity from risperidone and 9-hydroxy-risperidone. CYP2D6 inhibiting co-medications, such as paroxetine and levomepromazine, have been demonstrated to increase the concentration-dose ratio of risperidone and co-administration of fluoxetine increases the active moiety by 50-75%. Expectedly, CYP3A4 inducers (diet, rifampin, carbamazepine) have been demonstrated to reduce plasma concentrations of the active moiety, while CYP3A4 inhibitors (itraconazole, ketoconazole) produced the contrary effect.61 Due to the metabolic reliance on the kidneys and liver, patients with renal impairments experience a decrease in the active moiety by 60% and the mean free fraction plasma concentration increased by 35% in patients with hepatic impairments.62 Knockout mouse models have suggested that risperidone and paliperidone are substrates of Pglycoprotein (P-gp), the discharge transporter largely involved in the efflux of brain penetrants.63 It has been demonstrated that risperidone acts as a P-gp inhibitor to decrease active moiety efflux from the CNS (ER = 1.6); whereas, paliperidone is a weaker P-gp inhibitor and is more susceptible to P-gp transport (ER = 3.3). P-gp inhibitors (erythromycin, tamoxifen, rifampin) decrease the membrane transport of risperidone leading to higher concentrations and reduced ER.64 Pharmacology



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Although the precise pathophysiology of psychotic symptoms is unknown, there has been demonstrated influence by the dopaminergic, serotoninergic, and glutamatergic systems. Effective antipsychotics block the dopaminergic D2 receptors to some extent, which is associated with reduced psychotic symptoms as well as increased extrapyramidal side effects (EPS).48 Conversely, the hallmark of atypical antipsychotics is a weaker blockage at dopamine D2 receptors and stronger modulation at serotonergic (5-HT) receptors.65 The pharmacological profile for risperidone is characterized by a very high affinity for 5-HT2A serotonin receptor and moderately high affinity for the D2 dopamine receptor, H1 histamine receptor, and α1- and α2-adrenergic receptors.33 In vitro studies with rat brain preparations demonstrated that risperidone has a 10-20-fold greater affinity for the 5-HT2A receptor than the D2 receptor.66 Unlike other antipsychotics, risperidone lacks any affinity for muscarinic receptors and therefore produces no anticholinergic adverse effects.52,56 The binding affinities for risperidone and its active metabolite are displayed in Table 1. Table 1. Pharmacological Profile of Risperidone and Paliperidone.33 Receptor

Subtype

Dopaminergic

D1 D2 D2L D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-HT1E

Risperidone Ki (nM) 580 3.2 3.4 18 22 290 282 95 16 2948

5-HT2A

0.49

5-HT2C

19

5-HT4

2951

5-HT5A 5-HT6

658 4118

5-HT7

3.5

Adrenergic

α1a α2a α2b α2c

8 9.5 4.6 2.4

Histaminergic

H1

34

H2

855

M1

>10,000

Serotonergic

Muscarinic

Mode of Pharmacology antagonist antagonist antagonist antagonist antagonist antagonist antagonist antagonist antagonist antagonist inverse agonist inverse agonist inverse agonist antagonist antagonist irreversible antagonist antagonist antagonist antagonist antagonist inverse agonist inverse agonist

Paliperidone Ki (nM) 554 2.8 6.6 7.5 38 29 1030 111 7.3 1222 0.83 19 2884

1495 3425 3.8

11 111 4 2.7 34 4627

>10,000 8

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M2 M3 M4 M5

>10,000 >10,000 >10,000 >10,000

>10,000 >10,000 >10,000 >10,000

Early positron emission tomography (PET) studies revealed through the competitive binding displacement of serotonergic and dopaminergic radioligands that about 60% (ranging from 45-68%) of 5HT2 receptors in the frontal cortex and 50% (ranging from 40-64%) of the D2 dopamine receptors were occupied following 1 mg administration of risperidone.67 It is estimated that D2 occupancy rates of 6070% are necessary for an antipsychotic response and doses of risperidone in excess of 3 mg/day occupy 65-70% of D2 receptors.48,68 Reports have concluded that the high occupancy by 5-HT2A does not affect the D2 receptor occupancy required for antipsychotic effect.69 Risperidone’s combined antagonism at serotonin and dopamine receptors decreases the risk of EPS compared with conventional agents, with comparable relative risk of EPS to other atypical antipsychotics.70-71 The blockage of dopamine in the limbic system has been attributed to therapeutic efficacy, while its antagonism in the tuberoinfundibular and nigrostriatal tracts results in prolactin secretion and EPS, respectively.48 Due to risperidone’s mechanism of action through the blockage of D2 receptors, prolactin synthesis diminishes, resulting in hyperprolactinemia in addition to galactorrhea and amenorrhea.72 Structure-Activity Relationship This chemical structure of risperidone is a hybrid between a butyrophenone-type antipsychotic (2) and trazodone-like antidepressants (5).73 Atypical antipsychotics featuring indoles (ziprasidone and sertindole) and benzisoxazoles (risperidone, iloperidone, and paliperidone) are highly potent D2 antagonists.69 Studies utilizing ritanserin (7), a potent 5-HT2 antagonist, revealed alleviation of the negative symptoms in schizophrenia with fewer EPS than conventional antipsychotics. In order to merge the chemical motifs associated with 5-HT2A selectivity and D2 receptor blockade, a similar pyrimidinone side chain to ritanserin was retained and attached to a 1,2-benzisoxazol-3-yl piperidine, analogous to the substituted aryl piperidine in haloperidol.74 Structure-activity relationship (SAR) studies of butyrophenones revealed that an aliphatic amine is required, and cyclic amines gave the highest activity. Figure 3 highlights a generalized butyrophenone scaffold and antipsychotic activity is seen when Ar1 is an aromatic group, preferably with a para-fluoro substituent. Optimal activity is seen when X is a carbonyl, although alcohols, aryl groups, and a cyclized carbonyls are also well tolerated. When n is equal to three carbons optimal activity is achieved. The Ar2 group is necessary and should be aromatic, with one-atom linkers also displaying acceptable activity. Empirical SAR studies have concluded that the 4-aryl piperidino moiety shows high affinity for D2 and D3 receptors because it is superimposable with the phenethylamine backbone of dopamine.75



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Figure 3. Key SAR Features for Risperidone and a Generalized Butyrophenone Scaffold.75 The recently reported crystal structure of the dopamine D2 receptor in complex with risperidone revealed an unexpected mode of antipsychotic drug binding. The benzisoxazole moiety extends deep into the binding site to form a subpocket below the orthosteric site with Cys118, Thr119, Ser197, Phe198, Phe382, Phe390, and Trp385. Another hydrophobic pocket above the orthosteric site encloses the tertrahydropyrimidinone, and a salt bridge is formed between risperidone’s tertiary amine and Asp114.76 Docking assays were performed using risperidone and dopamine D3 crystallographic data to reveal two possible binding orientations in the receptor. In the first orientation, risperidone binds closer to the opening of the binding site and the benzisoxazole end points toward the bottom of the receptor cleft. In the second orientation, the molecule is situated deeper inside the receptor binding site with the benzisoxazole pointing toward the receptor surface.77 To evaluate the pharmacophore model of 5-HT2A, truncated and deconstructed variants of risperidone have been developed that retained nanomolar receptor binding affinity. Although this research is limited in its pharmacokinetic parameters, it nonetheless suggests that the multiple aromatic moieties are not essential for high 5-HT2A affinity.78 Adverse Effects and Dosage Risperidone is a relatively well-tolerated atypical antipsychotic and is less likely to induce extrapyramidal side effects (EPS) than conventional antipsychotics, eliciting dose-dependent EPS in 60-70% of patients at high dosages (>6 mg/day).30,72 The therapeutic index is limited with respect to efficacy and adverse effects by intraspecies variability, often resulting in tailoring dose and administration individually. Like other antipsychotics, risperidone can cause a broad range of side effects, commonly (≥10%) somnolence, increased appetite, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary incontinence, increased saliva, constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia. The commonly experienced adverse reactions from discontinuation were somnolence, nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia.34 Elevated prolactin levels are common with dopaminergic antagonism and can cause an array of symptoms, such as galactorrhea, gynecomastia, menstrual disturbances, sexual dysfunction, infertility, hirsutism and osteopenia in adults, as well as impaired growth and sexual maturation in children.72 Risperidone carries a black box warning indicating that elderly patients with dementia-related psychosis are at increased risk for cardiovascular adverse events and mortality. Regarding pregnancy, risperidone is classified as category C and should only be used if the benefit outweighs the risk to the fetus. The active moiety is excreted through breast-milk and therefore women taking the drug should not breastfeed. Risperidone has not been systematically studied for addiction or abuse, but there is currently none known.34 10 ACS Paragon Plus Environment

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Risperidone has numerous acceptable dosages and forms of administration, as depicted in Table 2. Therapies can be individualized as tablets (0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg), an oral solution (1 mg/mL), and orally disintegrating tablets (0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg).34 Additionally, long-acting injectable depots are available as intramuscular injections administered every two weeks in dosages of 12.5 mg, 25 mg, 37.5 mg, and 50 mg.79 Table 2. Dosage and Route of Administration of Risperidone by Indication and Population.34 Indication

Schizophrenia adults Schizophrenia adolescents Bipolar disorder adults Bipolar disorder children/adolescents Autism-related irritability

Effective Dose Range 4-16 mg/day

Initial Dose

Titration

Target Dose

2 mg/day

1-2 mg daily

4-8 mg daily

0.5 mg/day

0.5-1 mg daily

3 mg/day

1-6 mg/day

2-3 mg/day

1 mg daily

1-6 mg/day

1-6 mg/day

0.5 mg/day

0.25 mg/day (

Classics in Chemical Neuroscience: Risperidone - ACS Publications

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