Zotepine is an

atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurol ...

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

indicated for acute and chronic

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. It has been used in

Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...

since 1990 (although it has been discontinued in Germany) and

Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...

since 1982. Zotepine is not approved for use in the United States, United Kingdom, Australia, Canada or New Zealand.

Medical uses

Zotepine's primary use is as a treatment for schizophrenia although clinical trials have been conducted (with positive results) into its efficacy as an antimanic agent in patients with acute bipolar mania. 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 Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered. It is used primarily to treat people with schizophrenia and schizoaffective disorder who have ...

, slightly less effective than

olanzapine Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. It is also sometimes used off-label for treatment of chemotherapy-induced nausea and vomitin ...

and

risperidone Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is t ...

, approximately as effective as

paliperidone Paliperidone, sold under the brand name Invega among others, is an atypical antipsychotic. It is used for the treatment of schizophrenia and schizoaffective disorder. It is marketed by Janssen Pharmaceuticals. Paliperidone was approved by t ...

, and slightly more effective than

haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...

quetiapine Quetiapine ( ), sold under the brand name Seroquel among others, is an atypical antipsychotic medication used in the treatment of schizophrenia, bipolar disorder, bipolar depression, and major depressive disorder. Despite being widely prescri ...

, and

aripiprazole Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...

Side effects

; CommonBritish National Formulary 58. British Medical Association and Royal Pharmaceutical Society of Great Britain; 2009. *

Tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

Hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

Orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...

Palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...

Hyperprolactinaemia Hyperprolactinaemia (also spelled hyperprolactinemia) is a condition characterized by abnormally high levels of prolactin in the blood. In women, normal prolactin levels average to about 13 ng/mL, while in men, they average 5 ng/mL. ...

* Weight gain (produces a similar degree of weight gain to that seen with

and

treatment) *

Somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

(2nd highest effect size for causing sedation out of fifteen antipsychotics compared in a recent meta-analysis) *

Extrapyramidal side effects Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side ...

PSE PSE may refer to: Companies and organizations Stock exchanges * Pacific Stock Exchange, stock exchange in USA * Pakistan Stock Exchange, stock exchange of Pakistan * Palestine Securities Exchange, stock exchange in Palestine * Philippine Stock ...

(2nd largest

odds ratio An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of event A taking place in the presence of B, and the odds of A in the absence of B ...

for causing EPSE out of fifteen antipsychotics compared in a recent meta-analysis, second only to haloperidol) * Constipation *

Xerostomia Xerostomia, also known as dry mouth, is a subjective complaint of dryness in the mouth, which may be associated with a change in the composition of saliva, reduced salivary flow, or have no identifiable cause. This symptom is very common and is o ...

(dry mouth) * Blurred vision *

Hypersalivation Hypersalivation or hypersialosis is the excessive production of saliva. It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva.Medscape > HypersalivationBy Erica Brownfield. P ...

(drooling) *

Mydriasis Mydriasis is the Pupillary dilation, dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, Physical trauma, trauma, or the use of c ...

* Anxiety * Agitation * Rhinitis *

Sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...

Dyspnoea Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that c ...

* Diarrhoea * Influenza-like symptoms * Cough * Vertigo * Confusion *

Dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

* Flushing dry skin *

Arthralgia Arthralgia () literally means ' joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication Medication (also called medicament, medicine, pharmaceuti ...

Myalgia Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...

* Acne *

Conjunctivitis Conjunctivitis, also known as pink eye or Madras eye, is inflammation of the conjunctiva, the thin, clear layer that covers the white surface of the eye and the inner eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness ...

Thrombocythaemia In hematology, thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150 to 450 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 7 ...

;Unknown frequency *

QT interval The QT interval is a measurement made on an Electrocardiography, electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the QRS complex, Q wave to the end of the T wave, an ...

prolongation *

Hyperthermia Hyperthermia, also known as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme te ...

Hypothermia Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe ...

* Increased serum

creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an impor ...

Hyperglycaemia Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluco ...

Hypoglycaemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

Hyperlipidaemia Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...

* Thirst * Urinary incontinence ;Rare *

Angle-closure glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual ...

Agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing neutropenia in the circulating blood. I ...

Neutropaenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

Eosinophilia Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds . Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 billion/ L (1,500/ μL). The hypereosinophilic syndrome ...

Leukocytopenia Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * sk ...

Hypoesthesia Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to sensory stimuli. In everyday speech this is generally referred to as nu ...

Anaemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availab ...

Myoclonus Myoclonus is a brief, involuntary, irregular (lacking rhythm) twitching of a muscle, a joint, or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus ( myo- "muscle", clonus "spasm") describes a medical sign and, ...

* Myasthenia *

Alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...

Thrombocytopaenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coa ...

Bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

Epistaxis A nosebleed, also known as epistaxis, is an instance of bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significan ...

* Abdominal enlargement *

Deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...

* Paralytic

ileus Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction. The word 'ileus' derives . The term 'subileus' refers to a partial obstruction. Signs and symptoms S ...

Leukopenia Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * s ...

Tardive dyskinesia Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...

Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...

Laryngeal edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may inclu ...

Urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include urinary incont ...

* Depression *

Ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

Amnesia Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

* Seizure (dose-dependent risk) *

Metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...

Diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...

type II *

Cholestasis Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are: * obstructive type of cholestasis, where there is a mechanical blockage in the duct system that can occur from a gallston ...

* Increased liver enzymes * Photosensitivity * Exanthema * Pruritus *

Hypouricemia Hypouricemia or hypouricaemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper thre ...

Oedema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may inclu ...

Pharmacology

Pharmacodynamics

The antipsychotic effect of zotepine is thought to be mediated through

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s. Zotepine has a high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the D₁ and D₂ receptors. It also affects the 5-HT_2A, 5-HT_2C, 5-HT₆, and 5-HT₇ receptors. In addition, its active metabolite, norzotepine, serves as a potent

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...

Synthesis

The reaction of 2-chloroacetophenone with 4-chlorothiophenol gives a

thioether In organic chemistry, a sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, Volatile organic compound, volatile sulfides have ...

. This is treated with

morpholine Morpholine is an Organic compound, organic chemical compound having the chemical formula oxygen, O(carbon, Chydrogen, H2CH2)2nitrogen, NH. This heterocycle features both amine and ether functional groups. Because of the amine, morpholine is a bas ...

and sulfur in a Willgerodt–Kindler reaction to give a

phenylacetic acid Phenylacetic acid (conjugate base phenylacetate), also known by various synonyms, is an organic compound containing a phenyl functional group and a carboxylic acid functional group. It is a white solid with a strong honey-like odor. Endogenously ...

derivative after acid

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of the amide intermediate. Cyclization of this compound in the presence of

polyphosphoric acid In chemistry, a phosphoric acid, in the general sense, is a phosphorus acid, phosphorus oxoacid in which each phosphorus (P) atom is in the oxidation state +5, and is chemical bond, bonded to four oxygen (O) atoms, one of them through a double b ...

forms the

dibenzothiepin Dibenzothiepins are chemical compounds which are derivatives of thiepin with two benzene (here called benzo) rings. References

Dibenzothiepines, {{heterocyclic-stub ...

ring system of the drug. The

enol ether In organic chemistry an enol ether is an alkene with an alkoxy substituent. The general structure is R2C=CR-OR where R = H, alkyl or aryl. A common subfamily of enol ethers are vinyl ethers, with the formula ROCH=CH2. Important enol ethers incl ...

, 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.

Society and culture

Brand names

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