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Zotepine
Clinical data
Trade namesZoleptil
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances)[1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability7–13% (oral)[2]
MetabolismN-desmethylation to norzotepine (30-40%)[2]
Elimination half-life13.7–15.9 hours, 12 hours (Norzotepine)[2]
Excretion17% (Urine)[2]
Identifiers
  • 2-(3-chlorobenzo[b][1]benzothiepin-5-yl)oxy-N,N-dimethylethanamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.189.143 Edit this at Wikidata
Chemical and physical data
FormulaC18H18ClNOS
Molar mass331.86 g·mol−1
3D model (JSmol)
  • Clc2cc1C(/OCCN(C)C)=C\c3c(Sc1cc2)cccc3
  • InChI=1S/C18H18ClNOS/c1-20(2)9-10-21-16-11-13-5-3-4-6-17(13)22-18-8-7-14(19)12-15(16)18/h3-8,11-12H,9-10H2,1-2H3 checkY
  • Key:HDOZVRUNCMBHFH-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Zotepine is an atypical antipsychotic drug indicated for acute and chronic schizophrenia. It has been used in Germany since 1990 (although it has been discontinued in Germany) and Japan since 1982.

Zotepine is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.[3]

Medical uses

[edit]

Zotepine's primary use is as a treatment for schizophrenia[4] although clinical trials have been conducted (with positive results) into its efficacy as an antimanic agent in patients with acute bipolar mania.[5][6][7] In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, zotepine demonstrated medium-strong effectivity. Less effective than clozapine, slightly less effective than olanzapine and risperidone, approximately as effective as paliperidone, and slightly more effective than haloperidol, quetiapine, and aripiprazole.[8]

Side effects

[edit]
Common[2][4]
Unknown frequency[2][4]
Rare[2][4]

Pharmacology

[edit]

Pharmacodynamics

[edit]

The antipsychotic effect of zotepine is thought to be mediated through antagonist activity at dopamine and serotonin receptors. Zotepine has a high affinity for the D1 and D2 receptors. It also affects the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors.[10] In addition, its active metabolite, norzotepine, serves as a potent norepinephrine reuptake inhibitor.[11]

Macromolecule (Receptor or transporter protein) Ki [nM][10]
SERT 151
NET 530
DAT 3621
5-HT1A 470.5
5-HT1B 59.5
5-HT1D 119
5-HT1E 700
5-HT2A 2.7
5-HT2C 2.6
5-HT3 472
5-HT5A 29
5-HT6 6
5-HT7 12
α1A 7
α1B 5
α2A 180
α2B 5.35
α2C 106
M1 18
M2 140
M3 73
M4 77
M5 260
D1 71
D2 25
D2S 5.4
D2L 11
D3 6.4
D4 18
D5 248
H1 3.21
H2 500
H4 1977

Synthesis

[edit]

The reaction of 2-chloroacetophenone with 4-chlorothiophenol gives a thioether. This is treated with morpholine and sulfur in a Willgerodt–Kindler reaction to give a phenylacetic acid derivative after acid hydrolysis of the amide intermediate. Cyclization of this compound in the presence of polyphosphoric acid forms the dibenzothiepin ring system of the drug. The enol ether, zotepine, is produced when this is treated with the chloroethyl amine and potassium carbonate in methyl isobutyl ketone as solvent. Under these conditions, the undesired product of C-alkylation is minimised.[12][13][14]

Society and culture

[edit]

Brand names

[edit]

Brand names include Losizopilon (JP), Lodopin (ID, JP), Nipolept (DE†), Setous (JP), Zoleptil (CZ, PT, TR, UK†), Zotewin (IN); where † indicates a formulation that has been discontinued.

See also

[edit]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Zotepine

View on Grokipedia
from Grokipedia
Zotepine is a second-generation medication used primarily in the treatment of , particularly for managing both positive and negative symptoms, as well as acute . It is a dibenzothiepine derivative with the C₁₈H₁₈ClNOS, featuring a substituted structure that includes a chlorine atom at the 2-position and an N,N-dimethylaminoethoxy side chain. Developed in , zotepine is approved for clinical use in that country, some European nations (though discontinued in ), and parts of under brand names such as Lodopin, Zoleptil, and Nipolept, but it has not received approval from the U.S. as of 2025. Pharmacologically, zotepine exerts its therapeutic effects through antagonism at multiple receptors, including high-affinity blockade of D₁ and D₂ receptors, serotonin 5-HT₂A and 5-HT₂C receptors, and noradrenergic α₁ receptors, while also influencing H₁ sites to contribute to its properties. This multi-receptor profile distinguishes it from typical antipsychotics, potentially reducing the risk of extrapyramidal side effects, though it elevates extracellular levels of , noradrenaline, GABA, and glutamate in the without significantly altering serotonin. Clinical trials have demonstrated zotepine's efficacy as comparable to that of typical agents like and atypical drugs like in alleviating schizophrenic symptoms, with a number needed to treat of 3 over and 7 versus typical antipsychotics for clinically significant improvement. It shows particular promise for negative symptoms and treatment-resistant cases, though larger, long-term studies are recommended to confirm these benefits. Zotepine's side effect profile is generally favorable among atypicals, with lower incidences of such as (relative 0.73 versus typicals) and metabolic disturbances similar to other high- atypicals, but it carries a higher of sedation ( 4) and seizures, potentially linked to its enhancement of transmission. No significant differences in overall adverse events have been noted versus in short-term use, supporting its tolerability in acute settings.

Medical Aspects

Indications

Zotepine is approved for the treatment of acute and chronic in adults, addressing both positive symptoms such as hallucinations and delusions, as well as negative symptoms like social withdrawal and blunted affect. It is not approved for use in pediatric populations, with recommendations restricting its application to individuals aged 18 years and older. A 2013 multiple-treatments of 15 drugs ranked zotepine sixth in efficacy for overall symptom reduction in , indicating a medium-strong compared to (standardized mean difference of 0.49). This positioning places it above but below top-ranked agents like and . Additionally, a 2009 clinical review highlighted zotepine's particular effectiveness in alleviating negative symptoms, supported by its pharmacological profile that includes serotonin and antagonism. Investigated off-label uses include bipolar , where a pilot study demonstrated rapid symptom reduction in severely manic patients at a median dose of 250 mg/day. For treatment-resistant , evidence is limited but suggests potential benefits, particularly in managing persistent negative symptoms, as noted in clinical overviews.

Dosage and Administration

Zotepine is administered orally in tablet form, and it may be taken with or without food. For adults with , the recommended initial dose is 25 mg three times daily, with gradual increases at intervals of at least four days based on clinical response and tolerability. The typical maintenance dose ranges from 75 to 150 mg per day, divided into three doses, though higher doses up to a maximum of 100 mg three times daily (300 mg total) may be used in some cases under close supervision. In special populations, dose adjustments are necessary to minimize risks. For elderly patients, who may exhibit increased sensitivity, the initial dose should be 25 mg twice daily, with gradual titration to a maximum of 75 mg twice daily (150 mg total). In patients with hepatic or renal impairment, the initial dose is reduced to 25 mg twice daily, with a maximum of 75 mg twice daily, representing approximately a 50% reduction from standard adult dosing to account for altered clearance. Monitoring is essential due to zotepine's potential to affect cardiac and metabolic parameters. Baseline and periodic electrocardiogram (ECG) assessments are recommended to evaluate for prolongation, particularly before treatment initiation and during dose escalations, along with correction of any electrolyte imbalances. For metabolic risks associated with atypical antipsychotics, baseline and annual fasting plasma glucose and lipid profiles should be obtained, with more frequent monitoring in patients with predisposing factors such as or family history of diabetes. In cases of hepatic impairment, weekly are advised for the first three months of therapy.

Safety Profile

Adverse Effects

Zotepine, an , is associated with a range of adverse effects, the incidence of which varies based on dosage, duration of treatment, and patient factors. Common adverse effects, occurring in more than 10% of patients, include , which arises from its antagonism at H1 receptors and affects approximately 30% of users in short-term trials. Dizziness is also frequently reported, often linked to . is a notable concern, with clinical studies showing an average increase of 3.6 to 4.3 kg over several weeks to months and an incidence of up to 39% in comparative trials against other atypicals. Other common effects encompass and dry mouth, both reported across multiple studies. Serious adverse effects, with incidences typically between 1% and 10%, include (EPS) such as and , occurring in 8-29% of cases, though at rates lower than those seen with typical antipsychotics like . Seizures have been reported, with one study noting a 17.1% incidence of grand mal seizures. The risk of , a potentially irreversible , is reduced compared to first-generation agents due to zotepine's profile, but long-term exposure still warrants monitoring. Metabolic syndrome manifestations, including (incidence around 9%) and , contribute to broader cardiovascular risks over time. Rare adverse effects, affecting less than 1% of patients, include (NMS), characterized by , rigidity, and autonomic instability, with only isolated case reports documented. Blood dyscrasias have been noted as a potential hematologic . QT interval prolongation, which may lead to ventricular arrhythmias, has been observed in case reports and is exacerbated by doses exceeding 300 mg/day or concomitant QT-prolonging agents. Long-term use of zotepine elevates the of cardiovascular events, driven by cumulative metabolic changes and potential QT effects, necessitating regular monitoring of lipid profiles, glucose levels, and electrocardiograms. Abrupt discontinuation can precipitate withdrawal symptoms such as and rebound , highlighting the need for gradual tapering to mitigate these risks. Management strategies generally involve dose adjustment, symptomatic treatment (e.g., anticholinergics for EPS), and lifestyle interventions for weight and metabolic issues, with discontinuation considered if severe effects persist.

Contraindications and Interactions

Zotepine is contraindicated in patients with known to the drug or any of its components, as this can lead to severe allergic reactions. It is also absolutely contraindicated in individuals experiencing severe (CNS) depression or comatose states, due to the risk of exacerbating or other life-threatening effects. Additionally, zotepine should not be used in patients with pre-existing blood dyscrasias, such as or , as the medication may further impair function and increase risk. Relative precautions are advised for patients with , particularly those at risk for prolongation, which can predispose to ; ECG monitoring is recommended in such cases to mitigate risks associated with QT effects. Caution is warranted in individuals with a history of , as zotepine may lower the . Patients with prostatic hypertrophy should be monitored for due to the drug's properties. Furthermore, use in elderly patients with dementia-related is cautioned against, given the increased mortality risk observed with use in this population, often linked to cardiovascular or infectious complications. Drug interactions with zotepine primarily involve enzymes responsible for its metabolism. Inhibitors of , such as , can significantly increase zotepine plasma levels by reducing its clearance, potentially leading to enhanced toxicity. Conversely, inducers like may decrease zotepine efficacy by accelerating its metabolism and lowering systemic exposure. Additive QT prolongation can occur with antiarrhythmics such as quinidine or , heightening the risk of serious ventricular arrhythmias; concurrent use requires careful ECG surveillance. Other notable interactions include enhanced when zotepine is combined with alcohol, which potentiates CNS depressant effects and impairs psychomotor performance. Antihypertensive agents may interact additively to cause pronounced , necessitating monitoring during co-administration.

Pharmacology

Pharmacodynamics

Zotepine exerts its therapeutic effects primarily through antagonism at multiple receptors, particularly within the and serotonergic systems. It demonstrates potent antagonism at dopamine D1 and D2 receptors, with binding affinities (Ki values) ranging from 6.3 to 12 nM for the D2 receptor, contributing to its activity. Additionally, zotepine is a strong at the 5-HT2A serotonin receptor, with a Ki of 2.3 nM, which is higher affinity than its D2 binding and aligns with the receptor profile of . The also exhibits moderate antagonism at alpha-1 adrenergic receptors (Ki approximately 3-10 nM) and H1 (Ki around 3-8 nM), potentially influencing side effects such as and orthostatic . Zotepine also shows antagonism at serotonin 5-HT6 and 5-HT7 receptors, potentially contributing to its effects on cognitive and negative symptoms. A key component of zotepine's involves its major , norzotepine, which forms via N-demethylation and displays distinct activity. Norzotepine acts as a potent inhibitor of the (NET), with an in the low nanomolar range, thereby enhancing noradrenergic transmission. This norepinephrine reuptake inhibition complements zotepine's receptor antagonism and may augment antidepressant-like effects, particularly in addressing mood symptoms comorbid with . In schizophrenia, zotepine's mechanism aligns with the hypothesis, where D2 receptor blockade in the reduces hyperdopaminergic activity responsible for positive symptoms such as hallucinations and delusions. Concurrent 5-HT2A antagonism modulates serotonergic pathways, potentially improving negative symptoms like social withdrawal and blunted affect by enhancing prefrontal cortical release via indirect effects on nigrostriatal and mesocortical systems. Zotepine's profile is characterized by a balanced dopamine-serotonin receptor interaction that minimizes extrapyramidal side effects while maintaining efficacy.

Zotepine is rapidly and nearly completely absorbed from the after , achieving peak plasma concentrations within 2 to 4 hours. However, due to extensive first-pass metabolism in the liver, its is low, ranging from 7% to 13%. The drug exhibits a large apparent of approximately 109 L/kg, reflecting extensive penetration into tissues, including effective crossing of the blood-brain barrier as demonstrated by high brain-to-plasma ratios in preclinical studies. Zotepine and its primary , norzotepine, are approximately 97% bound to plasma proteins. Zotepine undergoes extensive hepatic metabolism primarily mediated by enzyme (predominant in N-demethylation to norzotepine and S-oxidation), with contributions from (primarily 2-) and (primarily 3-) in certain transformations. Key metabolic pathways include N-demethylation to the norzotepine (accounting for 30-40% of parent drug exposure), S-oxidation, aliphatic and aromatic , and subsequent conjugation; norzotepine retains pharmacological activity similar to the parent compound. Elimination of zotepine occurs mainly through fecal via biliary (predominant route for unchanged and metabolites), with lesser renal clearance of metabolites; only trace amounts of unchanged zotepine appear in . The terminal elimination ranges from 10 to 20 hours for zotepine and is similarly prolonged for norzotepine. Pharmacokinetic variability is influenced by factors such as , which induces activity and may thereby reduce plasma levels of zotepine, although some clinical studies report no statistically significant impact. Additionally, genetic polymorphisms in can alter metabolic rates, potentially necessitating individualized dosing adjustments to maintain therapeutic concentrations.

Chemistry

Structure and Properties

Zotepine is an classified as a dibenzothiepine , featuring a core structure consisting of two rings fused to a central thiepin ring. The includes a atom substituted at the 8-position and a 2-(dimethylamino)ethoxy attached at the 10-position, which contributes to its pharmacological properties. Its IUPAC name is 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethanamine. The of zotepine is C18H18ClNOS, with a molecular weight of 331.86 g/mol. It has an experimental logP of 4.25. Physically, zotepine appears as a white to off-white crystalline powder. It has a of approximately 90–93°C and a of 478°C. Zotepine exhibits low in , classifying it as a BCS Class II compound, but it is soluble in organic solvents such as and . Regarding stability, zotepine remains stable under normal storage conditions as a solid, showing no significant degradation after 72 hours of exposure to white fluorescent . However, in solution, it demonstrates sensitivity to , with approximately 25% observed upon . The compound is basic, with a pKa value of 8.92 for its strongest basic site, corresponding to the tertiary amine group.

Synthesis

The primary synthesis route for zotepine begins with the formation of a thioether precursor from 2-chloroacetophenone and 4-chlorothiophenol through a metal-catalyzed . This thioether undergoes the Willgerodt–Kindler reaction with and elemental to produce the corresponding thioamide, which is then hydrolyzed to the derivative. Intramolecular cyclization of the acid, typically facilitated by polyphosphoric acid at 80–90°C, yields the key intermediate 8-chlorodibenzo[b,f]thiepin-10(11H)-one with an overall yield of approximately 40% over these four steps. The final assembly of zotepine involves condensation of this ketone intermediate with 2-(dimethylamino)ethyl chloride in the presence of sodium hydride as a base, using a solvent mixture of benzene and dimethylformamide. The reaction proceeds at 50–100°C for several hours, forming the enol ether linkage at the 10-position and affording zotepine in 82% yield. Key steps in the core construction include the initial thioether formation to link the aromatic rings, followed by side-chain modification via the Willgerodt–Kindler rearrangement to enable cyclization. An alternative approach to the side chain integration employs reductive amination of an activated chloromethyl derivative with dimethylamine, though this variant is less commonly reported. Another synthetic pathway starts from 10,11-dihydrodibenzo[b,f]thiepin-10-one, where Grignard addition of 2-(dimethylamino)ethylmagnesium chloride to the carbonyl, followed by acid-catalyzed dehydration, generates the unsaturated enol structure of zotepine. The industrial , originally developed by Yoshitomi Pharmaceuticals, optimizes the overall 5–7 step sequence for scalability, achieving yields exceeding 70% through refined conditions such as controlled temperatures and solvent ratios in the ring-closure and stages.

History and Development

Discovery and Clinical Trials

Zotepine, a dibenzothiepine derivative, was developed by Fujisawa Pharmaceutical Co., Ltd. in during the 1970s as an targeting . The compound was designed to offer improved efficacy against negative symptoms compared to earlier , building on the thiepine structure to balance and serotonin receptor antagonism. Initial preclinical studies in the mid-1970s confirmed its antipsychotic potential through animal models of , leading to synthesis optimization for clinical evaluation. Early phase I and II clinical s conducted in during the late 1970s demonstrated zotepine's activity, with initial human dosing in small cohorts to assess safety and . These studies, involving doses up to 150 mg/day, reported rapid and tolerability in healthy volunteers and initial patient groups, paving the way for larger evaluations. Pivotal phase III s in the early 1980s, including double-blind comparisons against , established zotepine's superiority in reducing positive and negative symptoms of , with significant improvements in Brief Psychiatric Rating Scale (BPRS) scores observed within 4-8 weeks. For instance, a multicenter double-blind with 94 patients (zotepine 75-300 mg/day vs. thiothixene 15-60 mg/day) showed zotepine's in symptom reduction, though no significant differences in BPRS continuous data were pooled due to reporting issues (p<0.05 in some outcomes). Subsequent key studies further elucidated zotepine's profile. A clinical synthesized evidence from multiple trials, emphasizing its particular benefits for negative symptoms, such as emotional blunting and social withdrawal, with effect sizes comparable to in select cohorts. A 2013 multiple-treatments of 212 randomized trials involving over 43,000 participants ranked zotepine among the more effective antipsychotics for overall symptom control, demonstrating a standardized difference of 0.49 (95% CrI 0.31–0.66) versus on BPRS total scores. More recently, a 2019 network of 402 RCTs confirmed zotepine's efficacy against negative symptoms (SMD -0.33, 95% CrI -0.54 to -0.12 versus ), positioning it favorably against many second-generation agents for this domain. The 2021 Japanese guidelines for treatment recommend zotepine for maintenance therapy in responsive cases, noting its general tolerability. Major milestones include the initiation of human trials in the late and the completion of pivotal studies by 1981, culminating in Japan's first approval in 1982. Long-term studies, such as a 1-year in 253 patients (75–450 mg/day), demonstrated BPRS score reductions from a mean of 52 to 41, though 55% of participants withdrew, with low discontinuation rates due to adverse events among completers (approximately 24% overall withdrawal due to AEs). These findings underscored zotepine's potential for maintenance therapy, influencing its adoption in and .

Regulatory Approvals and Withdrawals

Zotepine received its initial regulatory approval in in February 1982 from the Ministry of Health, Labour and Welfare (MHLW), indicated for the treatment of . This approval was based on clinical trials demonstrating efficacy in managing schizophrenic symptoms. The drug remains available in under several brand names and continues to be marketed there as of 2025. In , zotepine was approved in 1990 by the Federal Institute for Drugs and Medical Devices (BfArM) for . However, it was discontinued from the German market around 2000 for commercial reasons, not due to safety or efficacy issues. As of 2025, it is no longer available in . The U.S. (FDA) never approved zotepine for marketing. In 1993, the FDA classified it as an inactive drug substance (Status I, Type II), determining that further development was not warranted due to insufficient supporting data from submitted studies. Zotepine was approved in the in 1998 but is no longer available there as of 2025; it has also not received approval in , , or as of 2025. Post-marketing surveillance has included reviews by the (EMA) in the 2010s, which monitored signals such as potential acute renal failure and confirmed no need for immediate regulatory action beyond periodic safety update reports. No major recalls have been issued globally. However, ongoing monitoring for is required, as Japanese post-marketing data from 2006 to 2009 reported 8 cases, including one fatal outcome, among approximately 702,000 treated patients. Zotepine remains approved and available in and select Asian markets, such as .

Society and Culture

Brand Names

Zotepine is available under several proprietary and names globally, primarily in Asian markets and historically in parts of , with manufacturing handled by major pharmaceutical companies and local generic producers. In , the original brand is Lodopin, originated and marketed by Astellas Pharma Inc. in tablet formulations of 25 mg, 50 mg, and 100 mg. Generic versions include Setous, another for the in the Japanese market, and Zotepine Tablets "TAKATA" (25 mg, 50 mg, and 100 mg). In , zotepine was marketed as Zoleptil and Nipolept by starting in 1990 but has since been discontinued. In , brands include Sirilept (25 mg, 50 mg, and 100 mg tablets), manufactured by Sun Pharmaceutical Industries Ltd. Zotepine is formulated exclusively as oral tablets in the aforementioned strengths, with no injectable preparations reported; generic versions are produced by regional firms in approved markets like and . Zotepine is classified as a prescription-only in countries where it is approved, including and , due to its status as a psychotropic under national drug regulations. In , it falls under of the Drugs and Rules, 1945, mandating sale only on the prescription of a registered practitioner. In , zotepine is regulated as a psychotropic substance under the Pharmaceuticals and Devices Act, requiring a physician's prescription for dispensing. As of 2025, zotepine remains widely available in , where it has been marketed since 1982, and in following its approval by the Central Drugs Standard Control Organization in 2010. Its availability is limited to select Asian markets and a few European countries, such as , where it is sold under the brand name Zoleptil as a prescription . It is not approved or available , where the FDA has classified it as an inactive drug substance since 1993, nor in major markets like the or , the latter having discontinued it after initial approval in 1990. Market trends for zotepine reflect its niche status, with primary sales concentrated in and steady growth from generic formulations following patent expiry in the late . No new regulatory approvals have occurred since 2010, constraining expansion to existing markets. Its limited global footprint is partly due to historical withdrawals in select regions, such as . Access barriers include strict import restrictions in non-approved countries, governed by international conventions on psychotropic substances, which prohibit personal importation without special permissions.

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