Pharmacological group: Antipsychotic drug (neuroleptic).
Pharmacological action: Antipsychotic drug for the treatment of bipolar disorder, schizophrenia and major depressive disorder.
Effects on receptors:
D1, D2, D3 and D4 receptors (antagonist)
Serotonin 5-HT 1A, 5-HT 2A, 5-HT 2C, and 5-HT 7 receptors (antagonist)
Alpha-1-adrenergic receptors and alpha-2-adrenergic receptors (antagonist)
H1 receptors (antagonist)
Receptors mACh (antagonist)
Quetiapine (known on the market under the names Seroquel, Xeroquel, Ketipinor), an atypical antipsychotic for the treatment of schizophrenia and bipolar disorder. The drug is also available in version XR and in combination with SSRIs is used to treat a major depressive disorder.
The annual sales of the drug is approximately $ 5.7 billion worldwide, and in the United States – $ 2.9 billion. The US patent expired in 2011, received an extension due to its pediatric exclusivity, and the patent was extended, respectively, until March 26, 2012. At the moment, the patent has already expired in Canada. Now there are several generics of Quetiapine, such as Quepin, Syquel and Ketipinor.
Fumarate Quetiapine is used to treat schizophrenia or bipolar disorder.
In the United States, quetiapine has been approved by the Food and Drug Administration (FDA) for the short-term treatment of schizophrenia and acute episodes associated with manic bipolar disorder (bipolar mania) and for the treatment of bipolar depression. In 2009, quetiapine ER was approved as an additional remedy for the treatment of major depressive disorder.
Quetiapine is also used not for its intended purpose in case of aggression, Alzheimer’s disease, anxiety, attention deficit disorder and hyperactivity disorder, bipolar disorder, dementia, depression, mood disorders, post traumatic stress disorders and insomnia, and as an agent for anger management.
It is not yet clear exactly which drugs are more effective – typical or atypical antipsychotics. They all have an equal withdrawal period and relapse symptoms when used at low and moderate doses.
In patients with bipolar disorder, the drug is used for depressive episodes, acute manic episodes associated with bipolar disorder I (as monotherapy or adjunctive therapy with lithium, valproate and lamotrigine), and maintenance therapy for bipolar I disorder (as adjunctive therapy with lithium or divalproate).
Quetiapine is ineffective in reducing the excitability among people with Alzheimer’s disease, whose share in drug sales was once 29%. Quetiapine worsens cognitive function in older people with dementia, and therefore its use among these categories of individuals is not recommended.
Quentiapine is sometimes used not for its intended purpose to treat conditions such as obsessive-compulsive disorder, post-traumatic stress disorder, autism, alcoholism, borderline personality disorder, depression, Tourette’s syndrome, musical hallucinations. The drug is also used as a sedative in people with sleep disorders or anxiety disorders. Use not for its intended purpose is not approved by the manufacturer. There has not yet been a convincing study of the side effects of long-term use of the drug not for its intended purpose, that is, for sleep disorders.
Seroquel: Side Effects
The most common side effect when taking Quetiapine is drowsiness. Other common side effects include: lethargy, fatigue, dry mouth, sore throat, dizziness, abdominal pain, constipation, stomach upset, orthostatic hypotension, inflammation or swelling of the paranasal sinuses or pharynx, blurred vision, increased appetite and weight.
Less common side effects include bruising and speech and language impairment. Ulcers in the oral cavity are a rare side effect. Very rare side effects include rapid swelling of the skin around the eyes, which visually accelerates the aging of the skin.
In recent years, disagreements have begun about the risk of death in quetiapine. At least six US military veterans who received cocktails with the drug, approved by military doctors for the treatment of post-traumatic stress disorder, died. Against AstraZeneca, approximately 10,000 claims were filed against individuals from the civilian population who encountered using the drug with problems such as slurred speech and chronic insomnia, and even death.
The drug is positioned as one of the most sedative antipsychotics, although this fact is disputed. During the first few days of taking the drug, and sometimes longer, users can feel tired. In the newest guidelines for the use of quetiapine against bipolar depression, it is generally recommended to take the whole dose before bedtime due to the sedative effect of the drug. Sedation may disappear or after a while, or because of changes in dosage, other, non-sedative, side effects may also occur.
Both typical and atypical antipsychotics can cause the development of tardive dyskinesia. According to one study, atypical drugs have a reduced coefficient of 3.9% compared to 5.5%. Although quetiapine and clozapine are atypical antipsychotics, switching to their use is a good way to minimize the symptoms of tardive dyskinesia caused by other atypical drugs.
Some patients can observe an increase in weight. It was found that quetiapine has a greater potential for weight gain than fluphenazine, haloperidol, loxapine, molindone, olanzapine, pimozide, risperidone, thioridazine, tiotiksen, trifluoperazine and ziprasidone, but smaller than aminazine, clozapine, perphenazine, and sertindole.
Studies of the drug carried out on hounds, say that as a result of admission in animals, there is a risk of developing cataracts. Although there are results of controlled trials of thousands of patients reporting a risk of developing cataracts in the human body, there is still no clear causal relationship between the use of quetiapine and this side effect. However, on the Seroquel website, users are advised to have regular half-yearly examinations from the oculist.
Like some other antipsychotics, quetiapine can reduce the threshold of convulsive alertness, and should be taken with caution in combination with drugs such as Bupropion.
Recent comparative studies of antipsychotics have shown that treatment alone with quetiapine is associated with an increased risk of mortality compared to other treatment methods analyzed (which is still better than a complete lack of antipsychotic medications).
Stop taking Seroquel should be gradually, with careful observation and with the appointment of a doctor, to avoid withdrawal or relapse symptoms.
The National Formulary of Britain recommends the gradual cessation of antipsychotic treatment to avoid acute withdrawal symptoms or a rapid recurrence of the disease. In connection with compensatory changes in dopamine, serotonin, adrenergic and histamine receptors in the central nervous system, with a sudden or too rapid decrease in the dose, withdrawal symptoms may occur. Despite the growing demand for safe and effective schedules for reducing the use of antipsychotics, there are currently no specific recommendations regarding their proven safety and efficacy.
Symptoms of withdrawal following the discontinuation of antipsychotics include nausea, vomiting, dizziness, sweating, dyskinesia, orthostatic hypotension, tachycardia, insomnia, nervousness, headache and anxiety. According to Eli Lilly’s internal documents, discontinuation of taking atypical antipsychotics similar to quetiapine may be associated with the development of psoriasis, gum disease and other inflammatory diseases, dyspepsia, headaches, increased blood sugar and other medical conditions. Some argue that additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common symptoms in stopping the use of neuroleptics. This suggests that the discontinuation process can in itself cause psychosis, producing psychotic symptoms even in previously healthy patients, indicating a possible pharmacologic origin of mental illness in a certain number of patients who have previously received antipsychotics. This issue has not yet been resolved, and remains highly controversial among specialists in the field of medicine and mental health.
In most cases, acute overdose of the drug Seroquel causes sedation, hypotension and tachycardia, cardiac arrhythmia. Among adults, coma and death were also observed. The concentration of quetiapine in serum or plasma in the range of 1-10 mg / l is considered relatively safe, while a concentration of 10-25 mg / l is associated with a risk of death.
Pregnancy and lactemia
The drug has a risk factor C during pregnancy. Quentiapine is toxic to the fetus and embryo, but no effect of the drug on animals has been demonstrated. The result of prolonged exposure to the development of a child is not clear, but its use in the third trimester is associated with a risk of abnormal muscle movements and manifestation of withdrawal symptoms. The following symptoms can occur in newborns: anxiety, eating disorders, hypertension, hypotension, respiratory failure, drowsiness and tremor. Hospitalization may be required. The drug is not recommended for taking during lactation, since it has the property of penetrating into breast milk.
Quetiapine is an antagonist of dopamine, serotonin and adrenergic receptors, and a powerful antihistamine drug with clinically insignificant anticholinergic properties. Quetiapine binds strongly to serotonin receptors, acting as a partial agonist of 5-HT 1A receptors. Serial scanning with PET (positron emission tomography) of D2 receptors showed that quetiapine is very rapidly separated from D2 receptors. Theoretically, this allows normal physiological leaps of dopamine to exhibit normal effects in such areas as nigrostriate and tuberoinfundibular pathways, minimizing the risk of side effects such as pseudo parkinsonism and increased prolactin levels. Some of the antagonist receptors (serotonin, noradrenaline) are actually autoreceptors, the blockade of which leads to an increase in the release of neurotransmitters.
Norquetiapine is an active metabolite of Quetiapine. The drug has most of the effects of quetiapine, having a similar potency, and is also a potent inhibitor of the reuptake of norepinephrine and muscarinic antagonists. Please note that the information given below is from another source (official information about the appointment of Seroquel), and the measures differ from the above (Ki vs. IC50). Also there are discrepancies in order of magnitude D1, alpha-1, H1 and M1.
At very low dosages, quetiapine acts primarily as a blocker of histamine receptors (antihistamine) and an alpha 1-adrenergic receptor blocker. When the dose increases, Quetiapine activates the adrenergic system and binds firmly to serotonin receptors and autoreceptors. At high doses, Quetiapine begins to block a significant number of dopamine receptors. It is not recommended to use low doses of quetiapine (<150 mg), except for the temporary titration period of the drug (less than 30 days).
In connection with compensatory changes in the dopamine, serotonin, adrenergic and histamine receptors in the central nervous system, a gradual dose reduction is recommended to minimize or completely avoid the following withdrawal symptoms: insomnia, nausea, vomiting, dizziness, sweating, orthostatic hypotension, tachycardia, as well as nervousness, headache and anxiety. These symptoms were observed in a small number of susceptible people taking quetiapine.
The National Formulary of Britain recommends a gradual withdrawal after the use of antipsychotics to avoid acute withdrawal symptoms or rapid recurrence.
In the second half of 2006, AstraZeneca introduced a new application for the drug, a prolonged version of Quetiapine for the treatment of schizophrenia in the United States, Canada and the European Union. AstraZeneca retains exclusive rights for this application on the market until 2017. Quetiapine prolonged action is known in the market as Seroquel XR, as well as Seroquel Prolong and Seroquel Depot.
May 18, 2007 AstraZeneca announced that the US FDA approved Seroquel XR for the treatment of acute schizophrenia. In the second quarter of 2007, during its conference, AstraZeneca announced plans to launch Seroquel XR in the US in August 2007. However, Seroquel XR became available in US pharmacies only on November 16, 2007, after it was approved by the FDA for use as a maintenance therapy for schizophrenia, in addition to the treatment of acute diseases. The company did not provide an excuse for delaying the launch of Seroquel XR. On September 27, 2007, the Canadian Ministry of Health approved the sale of Seroquel XR.
The Food and Drug Administration has approved Seroquel XR for the treatment of bipolar depression and bipolar mania in early October 2008. According to AstraZeneca, Seroquel XR is “the first drug approved by the Food and Drug Administration for the single treatment of acute and depressive and manic episodes associated with bipolar disorder.”
As of July 31, 2008, Handa Pharmaceuticals, based in Fremont, California, has announced the release of a new Fetal Extended-Release Quetiapine Fumarate Tablets application.
On December 1, 2008, Biovail announces the release of its prolonged version of Quetiapine, approved by the FDA. This version competed with Seroquel XR from AstraZeneca.
On December 24, 2008, AstraZeneca notified shareholders that the FDA requested additional information about the company’s application for the extended use of the prolonged version of Quetiapine in the treatment of depression.
In 1997, Quetiapine received initial approval from the US FDA as an agent for the treatment of schizophrenia. In 2004, the drug received an additional advantage as a treatment for mania associated with bipolar disorder. In 2007 and 2008, studies were conducted on the effectiveness of quetiapine in the treatment of generalized anxiety disorder and depression. In April 2009, the FDA’s Advisory Committee on Psychopharmacological Drugs held an open discussion on whether the results of the studies justify the FDA’s approval of the drug as a remedy against anxiety and depression, with the risks of metabolic side effects and tardive dyskinesia and sudden cardiac death.
AstraZeneca was sued by the US government (a lawsuit filed by Stefan P. Kruzewski on behalf of the state) about the marketing of Quetiapine. On October 29, 2009, an agreement was reached in the amount of $ 520 million.
In 2004, during a controversial clinical trial of the Seroquel drug at the University of Minnesota, a young man named Dan Markinson committed suicide while under compulsory detention in captivity. A group from the University of Minnesota on bioethics said that a number of disturbing ethical violations were recorded during the study, but the university refused to investigate.
Several US soldiers and veterans died as a result of taking Seroquel for the treatment of post-traumatic stress disorder.
Numerous lawsuits have been filed, related to the side effects of Quetiapine, in particular diabetes mellitus.
In Australia, Professor Patrick McGorry, a key mental health counselor, suggested testing the drug in Melbourne in 2011 to investigate whether quetiapine can reduce or delay risk in people aged 15 to 40 years with early signs of mental illness , developing into a later psychotic disorder. However, in July 2011 a group of psychiatrists, psychologists and researchers from Australia, New Zealand, Canada, the United Kingdom and the United States filed a complaint with the Ethics Committee of Health in Melbourne. They opposed the test, calling it “unethical” and “dangerous.”
In 2009, the documents used in the lawsuit against AstraZeneca indicated that Dr. Charles Schulz, head of the Department of Psychiatry at the University of Minnesota and consultant to AstraZeneca, distorted the data on the benefits of Seroquel, used in presentations and press releases of the study.
Quetiapine is not classified as a statutory substance, and “claims filed after self-administration of the drug are mainly associated with sedative and anxiolytic effects of Quetiapine (helping with problems with sleep or anxiety), and not with its antipsychotic properties.” In the medical literature there were reports of abuse of Quetiapine. In addition to oral administration, the preparation was also administered intranasally, inhaling the powdered tablets. There are reports of abuse with intravenous administration of the drug, as well as a joint intravenous introduction of cocaine, the so-called “Q-Ball”. In a 2004 letter to the editor of the American Journal of Psychiatry, interesting statistics were cited that up to 30% of prisoners needing psychiatric care in Los Angeles prison imitated the psychotic symptoms of the disease in order to get Quetiapine. Cases of drug abuse, also known as “sedative”, “sleepy berries”, or “Suzy-Kew”, are more often found in prisons due to the fact that it is regularly prescribed as a sedative in the absence of other more popular psychotropic substances in prison. In a letter sent to the editorial board of the American Journal of Psychiatry in January 2007, “the need for additional studies of Quetiapine as a drug that causes addiction” was stated. The authors of the letter were doctors working within the framework of the criminal justice system of the State of Ohio. They report that “the prisoners … threatened legal action and even suicide when they stopped giving Quetiapine,” and that “no similar behavior was observed when using other second-generation antipsychotics of comparable efficacy.” It was also reported that when the drug was used together with methadone, users experienced euphoria similar to opioid.
The Case of Nurofen Plus Falsification
In August 2011, the Agency for the Regulation of Medicines and Medicines and Products of Great Britain (MHRA) issued urgent warnings after reports that some Nurofen Plus parties contain a Seroquel XL.
After this message, Reckitt Benckiser Ltd (Great Britain) received reports on incorrect labels on the cardboard boxes of two additional Nurofen Plus lots. One of the batches contained a 50-mg Seroquel XL tablet, and the other contained 100-mg Pfizer Neurontin capsules.
After that, Reckitt Benckiser (UK) Ltd decided to release the entire remaining stock of Nurofen Plus tablets in packages of all sizes. This issue was traced to the shelves of stores.