What is Clozapine?

Introduction

Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson’s disease. Clozapine is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, after resistance to earlier neuroleptic treatment is established.

The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark study in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis who had already shown an inadequate response to other antipsychotics. While there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response. The use of clozapine is associated with multiple improved outcomes, including a reduced rate of all-cause mortality, suicide and hospitalisation. In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs. In a 2021 UK study, the majority of patients (over 85% of respondents) who took clozapine preferred it to their previous therapies, felt better on it and wanted to keep taking it. In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness.

Compared to other antipsychotics, clozapine has an increased risk of blood dyscrasias, in particular agranulocytosis, in the first 18 weeks of treatment. After one year, this risk reduces to that associated with most antipsychotics. Clozapine’s use is therefore reserved for people who have not responded to two other antipsychotics and is only done with stringent blood monitoring. Overall, despite the concerns relating to blood and other side effects, clozapine use is associated with a reduced mortality, especially from suicide which is a major cause of premature death in people with schizophrenia. The risk of clozapine related agranulocytosis and neutropenia warranted the mandatory use of stringent risk monitoring and management systems, which have reduced the risk of death from these adverse events to around 1 in 7,700. The association between clozapine use and specific bloods dyscrasias was first noted in the 1970s when eight deaths from agranulocytosis were noted in Finland. At the time it was not clear if this exceeded the established rate of this side effect which is also found in other antipsychotics and although the drug was not completely withdrawn, its use became limited. Clozapine became widely available in the early 1990s and remains the only treatment likely to be effective in treating resistant schizophrenia.

Common adverse effects include drowsiness, constipation, hypersalivation (increased saliva production), tachycardia, low blood pressure, blurred vision, weight gain, and dizziness. Clozapine is not normally associated with tardive dyskinesia (TD) and is recommended as the drug of choice when this is present, although some case reports describe clozapine-induced TD. Other serious risks include seizures, inflammation of the heart, high blood sugar levels, constipation. The use of this drug can rarely result in clozapine-induced gastric hypomotility syndrome which may lead to bowel obstruction and death, and in older people with psychosis, as a result of dementia it may lead to an increased risk of death. The mechanism of action is not entirely clear in the current medical literature. Clozapine is on the World Health Organization’s List of Essential Medicines. It is available as a generic medication.

Brief History

Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine. The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967 Wander AG was acquired by Sandoz. Further trials took place in 1972 when clozapine was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany and in Finland in 1975. Early testing was performed in the United States around the same time. In 1975, 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, led to concern. Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period. The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic diversity in the region. Whilst the drug continued to be manufactured by Sandoz, and remained available in Europe, development in the US halted.

Interest in clozapine continued in an investigational capacity in the United States because, even in the 1980s, the duration of hospitalisation, especially in State Hospitals for those with treatment resistant schizophrenia might often be measured in years rather than days. The role of clozapine in treatment resistant schizophrenia was established by the landmark Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double-blind design with the power to demonstrate superiority over standard antipsychotic treatment. The inclusion criteria were patients who had failed to respond to at least three previous antipsychotics and had then not responded to a single blind treatment with haloperidol (mean dose 61 mg +/- 14 mg/d). Two hundred and sixty-eight were randomised were to double blind trials of clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d). 30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses’ Observation Scale for Inpatient Evaluation; this improvement included “negative” as well as positive symptom areas. Following this study, the US Food and Drug Administration (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.

In December 2002, clozapine was approved in the US for reducing the risk of suicide in people with schizophrenia or schizoaffective judged to be at chronic risk for suicidal behaviour. In 2005, the FDA approved criteria to allow reduced blood monitoring frequency. In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared Patient Registry Called The Clozapine REMS Registry. Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardised.

Chemistry

Clozapine is a dibenzodiazepine that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C).[3] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).

Clinical Uses

Schizophrenia

Clozapine is usually used for people diagnosed with schizophrenia who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson’s Disease. It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, supported by systematic reviews and meta-analysis. Whilst all current guidelines reserve clozapine to individuals when two other antipsychotics evidence indicates that clozapine might be used as a second line drug. Clozapine treatment has been demonstrated to produced improved outcomes in multiple domains including; a reduced risk of hospitalisation, a reduced risk of drug discontinuation, a reduction in overall symptoms and has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia. Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics. Very long term follow-up studies reveal multiple benefits in terms of reduced mortality, with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of suicide or attempted suicide. Clozapine has a significant anti-aggressive effect. Clozapine is widely used in secure and forensic mental health settings where improvements in aggression, shortened admission and reductions in restrictive practice such as seclusion have been found. In secure hospitals and other settings clozapine has also been used in the treatment of borderline and antisocial personality disorder when this has been associated with violence or self-harm. Although oral treatment is almost universal clozapine has on occasion been enforced using either nasogastric or a short acting injection although in almost 50% of the approximately 100 reported cases patients agreed to take oral medication prior to the use of a coercive intervention. Clozapine has also been used off-label to treat catatonia with success in over 80% of cases.

Bipolar Disorder

On the basis of systematic reviews clozapine is recommended in some treatment guidelines as a third or fourth line treatment for bipolar disorder. Bipolar disorder is an unlicensed indication for clozapine.

Severe Personality Disorders

Clozapine is also used in emotionally unstable personality disorder and a randomised controlled trial is currently underway. The use of clozapine to treat personality disorder is uncommon and unlicensed.

Initiation

Whilst clozapine is usually initiated in hospital setting community initiation is also available. Before clozapine can be initiated multiple assessments and baseline investigations are performed. In the UK and Ireland there must be an assessment that the patient satisfies the criteria for prescription; treatment resistant schizophrenia, intolerance due to extrapyramidal symptoms of other antipsychotics or psychosis in Parkinson’s disease. Establishing a history of treatment resistance may include careful review of the medication history including the durations, doses and compliance of previous antipsychotic therapy and that these did not have an adequate clinical effect. A diagnostic review may also be performed. That could include review of antipsychotic plasma concentrations if available. The prescriber, patient, pharmacy and the laboratory performing blood counts are all registered with a specified clozapine provider who must be advised that there is no history of neutropenia from any cause. The clozapine providers collaborate by sharing information regarding patients who have had clozapine related neutropenia or agranulocytosis so that clozapine cannot be used again on license. Clozapine may only be dispensed after a satisfactory blood result has been received by the risk monitoring agency at which point an individual prescription may be released to an individual patient only.

Baseline tests usually also include; a physical examination including baseline weight, waist circumference and BMI, assessments of renal function and liver function, an ECG and other baseline bloods may also be taken to facilitate monitoring of possible myocarditis, these might include C reactive protein (CRP) and troponin. In Australia and New Zealand pre-clozapine echocardiograms are also commonly performed. A number of service protocols are available and there are variations in the extent of preclozapine work ups. Some might also include fasting lipids, HbA1c and prolactin. At the Maudsley Hospital in the UK the Treat service also routinely performs a wide variety of other investigations including multiple investigations for other causes of psychosis and comorbidities including; MRI brain imaging, thyroid function tests, B12, folate and serum calcium levels, infection screening for blood borne viruses including Hepatitis B and C, HIV and syphilis as well as screening for autoimmune psychosis by anti-NMDA, anti-VGKC and Anti-nuclear Antibody screening. Investigations used to monitor the possibility of clozapine related side effects such as myocarditis are also performed including baseline troponin, CRP and BNP and for neuroleptic malignant syndrome CK.

The dose of clozapine is initially low and gradually increased over a number of weeks. Initial doses may range from 6.5 to 12.5 mg/d increasing stepwise typically to doses in the range of 250-350 mg per day at which point an assessment of response will be performed. In the UK the average clozapine dose is 450 mg/d. But response is highly variable and some patients respond at much lower doses and vice versa.

Monitoring

During the initial dose titration phase the following are typically monitored; usually daily at first; pulse, blood pressure and since orthostatic hypotension can be problematic this should be monitored both sitting and standing. If there is a significant drop then the rate of the dose increase may be slowed, temperature.

Weekly tests include; Mandatory full blood counts are performed weekly for the first 18 weeks. In some services there will also be monitoring of markers that might indicate myocarditis; troponin, CRP and BNP although the exact tests and frequency vary between services. Weight is usually measured weekly.

Thereon other investigations and monitoring will always include full blood counts (fortnightly for 1 year then monthly). Weight, waist circumference, lipids and glucose or HbA1c may also be monitored.

Clozapine Response and Treatment Optimisation

As with other antipsychotics, and in contrast to received wisdom, responses to clozapine are typically seen soon after initiation and often within the first week. That said responses, especially those which are partial, can be delayed. Quite what an adequate trial of clozapine is, is uncertain but a recommendation is that this should be for at least 8 weeks on a plasma trough level above 350-400 micro g/L. There is considerable inter-individual variation. A significant number of patients respond at lower and also much higher plasma concentrations and some patients, especially young male smokers may never achieve these plasma levels even at doses of 900 mg/day. Options then include either increasing the dose above the licensed maximum or the addition of a drug that inhibits clozapine metabolism. Avoiding unnecessary polypharmacy is a general principle in drug treatment.

Optimising Blood Sampling

The neutrophil cut off for clozapine have shown an exceptional ability to mitigate the risk of neutropenia and agranulocytosis. There is a significant margin of safety. Some patients may have marginal neutrophil counts before and after initiation and they are at risk of premature clozapine discontinuation. A knowledge of neutrophil biology allows blood sampling optimisation. Neutrophils show a diurnal variation in response to the natural cycle of G-CSF production, they are increased in the afternoons, they are also mobilised into the circulation after exercise and smoking. Simply shifting blood sampling has been shown to avoid unnecessary discontinuations, especially in black populations. However this is a disruption to usual hospital practice. Other practical steps are to ensure that blood results become available in hours and when senior staff are available.

Underuse of Clozapine

Clozapine is widely recognised as being underused with wide variation in prescribing, especially in patients with African heritage.

Psychiatrists prescribing practices have been found to be the most significant variable regarding variance in its use. Surveys of psychiatrists attitudes to clozapine have found that many had little experience in its use, over estimated the incidence and were fearful of side effects, and did not appreciate that many patients prefer to take clozapine than other antipsychotics, are reluctant to prescribe clozapine, had little experience in its use and believed that patients treated with clozapine were less satisfied than those treated with other antipsychotics. In contrast to many psychiatrists expectations most patients believe that the blood testing and other difficulties are worth the multiple benefits that they perceive. Whilst psychiatrists fear the severe adverse effects such as agranulocytosis, patients are more concerned about hypersalivation. Clozapine is no longer actively marketed and this may also be one of the explanations for its underuse.

Despite the strong evidence and universal endorsement by national and international treatment guidelines and the experiences of patients themselves, most people eligible for clozapine are not treated with it. A large study in England found that approximately 30% of those eligible for clozapine were being treated with it. Those patients that do start clozapine usually face prolonged delay, multiple episodes of psychosis and treatments such as high dose antipsychotics or polypharmacy. Instead of two previous antipsychotics many will have been exposed to ten or more drugs which were not effective. In a study of 120 patients conducted in four hospitals in South-East London, found a mean of 9.2 episodes of antipsychotic prescription before clozapine was initiated and the mean delay in using clozapine was 5 years. Treatments that have no evidence base or are regarded as actively harmful are used instead multiple and or high-dose treatment.

Racial Disparity in the Use of Clozapine

A general finding in healthcare provision is that minority groups receive inferior treatment; this is a particular finding in the US. In the US a general finding is that compared to their white peers African American people are less likely to be prescribed the second generation antipsychotics, which are more expensive than alternatives and this was even apparent and especially so for clozapine when comparison was made in the Veterans Affairs medical system and when differences regarding socioeconomic factors were taken into account. As well as being less likely to start clozapine black patients are more likely to stop clozapine, possibly on account of benign ethnic neutropenia.

Benign Ethnic Neutropenia

Benign reductions in neutrophils are observed in individuals of all ethnic backgrounds ethnic neutropenia (BEN), neutropenia without immune dysfunction or increased liability to infection is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. BEN is associated with several ethnic groups, but in particular those with Black African and West African ancestry. A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations. For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use as the thresholds did not take BEN into account. Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 109/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima. But even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. The Duffy-Null polymorphism, which protects against some types of malaria, is predictive of BEN.

Adverse Effects

Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five black box warnings, including:

  1. Severe neutropenia (low levels of neutrophils);
  2. Orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting;
  3. Seizures;
  4. Myocarditis (inflammation of the heart); and
  5. Risk of death when used in elderly people with dementia-related psychosis.

Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.

Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia, is below that of typical antipsychotics; this may be due to clozapine’s anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine. Sexual problems, like retrograde ejaculation, have been reported while taking clozapine. Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.

Neutropenia and Agranulocytosis

Clozapine Induced Neutropenia (CIN) occurs in approximately 3.8% of cases and Clozapine Induced Agranulocytosis (CIA) in 0.4%. These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory absolute neutrophil count (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS). The exact schedules and blood count thresholds vary internationally and the thresholds at which clozapine can be used in the US has been lower than those currently used in the UK and Australasia for some time. The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7,700 patients treated. Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks. After one year of treatment these risks reduce markedly to that seen in other antipsychotic drugs 0.01% or about 1 in 10,000 and the risk of death is markedly lower still. When reductions in neutrophil levels are noted on regular blood monitoring then, depending on the value, monitoring may be increased or, if the neutrophil count is sufficiently low, then clozapine is stopped immediately and can then no longer be used within the medicinal licence. Stopping clozapine almost always results in resolution of the neutrophil reduction. However severe agranulocytosis can result in spontaneous infection and death, is a severe decrease in the amount of a specific kind of white blood cell called granulocytes. Clozapine carries a black box warning for drug-induced agranulocytosis. Rapid point-of-care tests may simplify the monitoring for agranulocytosis.

Clozapine Rechallenge

A clozapine “rechallenge” is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce clozapine but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had clozapine stopped according to the US criteria only 7 would have had clozapine stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use clozapine without difficulty and only 1 had a fall in neutrophils below the US cut off. Other approaches have included the use of other drugs to support neutrophil counts including lithium or granulocyte colony-stimulating factor (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited.

Cardiac Toxicity

Clozapine can rarely cause myocarditis and cardiomyopathy. A large meta-analysis of clozapine exposure to over 250,000 people revealed that these occurred in approximately 7 in 1,000 patients treated and resulted in death in 3 and 4 in 10,000 patients exposed respectively and although myocarditis occurred almost exclusively within the first 8 weeks of treatment, cardiomyopathy can occur much later on. First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness. Signs of heart failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate. A large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives. Rechallenge after clozapine induced myocarditis has been performed and a protocol for this specialist approach has been published. A systematic review of rechallenge after myocarditis has show success in over 60% of reported cases.

Gastrointestinal Hypomotility

Another under-recognised and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, faecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers. Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis. A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication. Monitoring bowel function and the pre-emptive use of laxatives for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae.

Hypersalivation

Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%). The saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day. While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for hypersalivation. Clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication. Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as hyoscine, diphenhydramine and topical anticholinergic medications like ipratropium bromide. Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.

Central Nervous System

CNS side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paraesthesia, status epilepticus, and obsessive compulsive symptoms. Similar to other antipsychotics clozapine rarely has been known to cause neuroleptic malignant syndrome.

Urinary Incontinence

Clozapine is linked to urinary incontinence, though its appearance may be under-recognised.

Withdrawal Effects

Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhoea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation. Abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis. Doctors have recommended that patients, families, and caregivers be made aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.

Weight Gain and Diabetes

In addition to hyperglycaemia, significant weight gain is frequently experienced by patients treated with clozapine. Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.

Pneumonia

International adverse drug effect databases indicate that clozapine use is associated with a significantly increased incidence of and death from pneumonia and this may be one of the most significant adverse events. The mechanisms for this are unknown although it has been speculated that it may be related to hypersalivation, immune effects of clozapine’s effects on the resolution of inflammation.

Overdose

Symptoms of overdose can be variable, but often include; sedation, confusion, tachycardia, seizures and ataxia. Fatalities have been reported due to clozapine overdose, though overdoses of greater than 5000 mg have been survived.

Drug Interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.

When carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine. Patients should be monitored for “decreased therapeutic effects of clozapine if carbamazepine” is started or increased. If carbamazepine is discontinued or the dose of carbamazepine is decreased, therapeutic effects of clozapine should be monitored. The study recommends carbamazepine to not be used concurrently with clozapine due to increased risk of agranulocytosis.

Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in subjects concurrently taking ciprofloxacin. Thus, the prescribing information for clozapine recommends “reducing the dose of clozapine by one-third of original dose” when ciprofloxacin and other CYP1A2 inhibitors are added to therapy, but once ciprofloxacin is removed from therapy, it is recommended to return clozapine to original dose.

Pharmacology

Pharmacodynamics

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.

Clozapine is an antagonist at the 5-HT2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.

A direct interaction of clozapine with the GABAB receptor has also been shown. GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.

Pharmacokinetics

The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. However, it was shown that co-administration of food decreases the rate of absorption. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).

Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and faeces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g. cigarette smoke) or inhibit (e.g. theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.

Clozapine and norclozapine (desmethyl-clozapine) plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age. Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimisation.

Society and Culture

Economics

Despite the expense of the risk monitoring and management systems required, clozapine use is highly cost effective; with a number of studies suggesting savings of tens of thousands of dollars per patient per year compared to other antipsychotics as well as advantages regarding improvements in quality of life. Clozapine is available as a generic medication.

Clozapine in the Arts

Carrie Mathison, a fictional CIA operative in the television series Homeland, secretly takes clozapine supplied by her sister for the treatment of bipolar disorder.

In the film Out of Darkness, Diana Ross played the protagonist Paulie Cooper, “a paranoid schizophrenic” who is depicted as having a dramatic improvement on clozapine.

In the television series Last Man On Earth (2015) the character Melissa has a psychotic episode and returns home and starts acting how she did pre-pandemic. Her boyfriend Todd sees her take a medication in the morning and asks her what it is. All she will say is “Santas Penis”. Todd searches medication books and finds clozapine = Clause a peen.

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What is an Atypical Antipsychotic?

Introduction

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 major tranquilisers and neuroleptics, although the latter is usually reserved for the typical antipsychotics) largely introduced after the 1970s and used to treat psychiatric conditions.

Some atypical antipsychotics have received regulatory approval (e.g. by the Food and Drug Administration (FDA) of the US, the Therapeutic Goods Administration (TGA) of Australia, the Medical and Healthcare Products Regulatory Agency (MHRA) of the UK) for schizophrenia, bipolar disorder, autism, and as an adjunct in major depressive disorder.

Both generations of medication tend to block receptors in the brain’s dopamine pathways. Atypicals are less likely than haloperidol – the most widely used typical antipsychotic – to cause extrapyramidal motor control disabilities in patients such as unsteady Parkinson’s disease-type movements, body rigidity, and involuntary tremors. However, only a few of the atypicals have been demonstrated to be superior to lesser-used, low-potency first-generation antipsychotics in this regard.

As experience with these agents has grown, several studies have questioned the utility of broadly characterising antipsychotic drugs as “atypical/second generation” as opposed to “first generation,” noting that each agent has its own efficacy and side-effect profile. It has been argued that a more nuanced view in which the needs of individual patients are matched to the properties of individual drugs is more appropriate. Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects, including tardive dyskinesia (a serious movement disorder), neuroleptic malignant syndrome, and increased risk of stroke, sudden cardiac death, blood clots, and diabetes. Significant weight gain may occur. Critics have argued that “the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.”

Brief History

The first major tranquiliser or antipsychotic medication, chlorpromazine (Thorazine), a typical antipsychotic, was discovered in 1951 and introduced into clinical practice shortly thereafter. Clozapine (Clozaril), an atypical antipsychotic, fell out of favour due to concerns over drug-induced agranulocytosis. Following research indicating its effectiveness in treatment-resistant schizophrenia and the development of an adverse event monitoring system, clozapine re-emerged as a viable antipsychotic. According to Barker (2003), the three most-accepted atypical drugs are clozapine, risperidone, and olanzapine. However, he goes on to explain that clozapine is usually the last resort when other drugs fail. Clozapine can cause agranulocytosis (a decreased number of white blood cells), requiring blood monitoring for the patient. Despite the effectiveness of clozapine for treatment-resistant schizophrenia, agents with a more favourable side-effect profile were sought-after for widespread use. During the 1990s, olanzapine, risperidone, and quetiapine were introduced, with ziprasidone and aripiprazole following in the early 2000s. The atypical anti-psychotic paliperidone was approved by the FDA in late 2006.

The atypical antipsychotics have found favour among clinicians and are now considered to be first-line treatments for schizophrenia and are gradually replacing the typical antipsychotics. In the past, most researchers have agreed that the defining characteristics of atypical antipsychotics are the decreased incidence of extrapyramidal side effects (EPS) and an absence of sustained prolactin elevation.

The terminology can still be imprecise. The definition of “atypicality” was based upon the absence of extrapyramidal side effects, but there is now a clear understanding that atypical antipsychotics can still induce these effects (though to a lesser degree than typical antipsychotics). Recent literature focuses more upon specific pharmacological actions and less upon categorization of an agent as “typical” or “atypical”. There is no clear dividing line between the typical and atypical antipsychotics therefore categorisation based on the action is difficult.

More recent research is questioning the notion that second-generation antipsychotics are superior to first generation typical anti-psychotics. Using a number of parameters to assess quality of life, Manchester University researchers found that typical antipsychotics were no worse than atypical antipsychotics. The research was funded by the National Health Service (NHS) of the UK. Because each medication (whether first or second generation) has its own profile of desirable and adverse effects, a neuropsychopharmacologist may recommend one of the older (“typical” or first generation) or newer (“atypical” or second generation) antipsychotics alone or in combination with other medications, based on the symptom profile, response pattern, and adverse effects history of the individual patient.

Medical Uses

Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder. They are also frequently used to treat agitation associated with dementia, anxiety disorder, autism spectrum disorder, and obsessive-compulsive disorder (an off-label use). In dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others.

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication, which can reduce the positive symptoms of schizophrenia in about 8-15 days. Antipsychotics only appear to improve secondary negative symptoms of schizophrenia in the short term and may worsen negative symptoms overall. Overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia.

There is very little evidence on which to base a risk and benefit assessment of using antipsychotics for long-term treatment.

The choice of which antipsychotic to use for a specific patient is based on benefits, risks, and costs. It is debatable whether, as a class, typical or atypical antipsychotics are better. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. There is a good response in 40-50% of patients, a partial response in 30-40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two of three different antipsychotics) in the remaining 20%. Clozapine is considered a first choice treatment for treatment resistant schizophrenia, especially in the short term; in the longer-terms the risks of adverse effects complicate the choice. In turn, olanzapine, risperidone, and aripiprazole have been recommended for the treatment of first-episode psychosis.

Efficacy in the Treatment of Schizophrenia

The utility of broadly grouping the antipsychotics into first generation and atypical categories has been challenged. It has been argued that a more nuanced view, matching the properties of individual drugs to the needs of specific patients is preferable. While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and extrapyramidal symptoms in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring. In 2005 the US government body NIMH (National Institute for Mental Health) published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project). This study compared several atypical antipsychotics to an older, mid-potency typical antipsychotic, perphenazine, among 1,493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 9.4 lbs over 18 months) and increases in glucose, cholesterol, and triglycerides. No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine (a result supported by a meta-analysis by Leucht et al. published in The Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002). A phase 2 part of this CATIE study roughly replicated these findings. Compliance has not been shown to be different between the two types. Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to question the distinction between the two classes.

It has been suggested that there is no validity to the term “second-generation antipsychotic drugs” and that the drugs that currently occupy this category are not identical to each other in mechanism, efficacy, and side-effect profiles.

Bipolar Disorder

In bipolar disorder, SGAs are most commonly used to rapidly control acute mania and mixed episodes, often in conjunction with mood stabilizers (which tend to have a delayed onset of action in such cases) such as lithium and valproate. In milder cases of mania or mixed episodes, mood stabiliser monotherapy may be attempted first. SGAs are also used to treat other aspects of the disorder (such as acute bipolar depression or as a prophylactic treatment) as adjuncts or as a monotherapy, depending on the drug. Both quetiapine and olanzapine have demonstrated significant efficacy in all three treatment phases of bipolar disorder. Lurasidone (trade name Latuda) has demonstrated some efficacy in the acute depressive phase of bipolar disorder.

Major Depressive Disorder

In non-psychotic major depressive disorder (MDD), some SGAs have demonstrated significant efficacy as adjunctive agents; and, such agents include:

  • Aripiprazole.
  • Brexpiprazole.
  • Olanzapine.
  • Quetiapine.
  • Ziprasidone.

Whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD. Olanzapine/fluoxetine is an efficacious treatment in both psychotic and non-psychotic MDD.

Aripiprazole, brexpiprazole, olanzapine, and quetiapine have been approved as adjunct treatment for MDD by the FDA in the United States. Quetiapine and lurasidone have been approved, as monotherapies, for bipolar depression, but as of present, lurasidone has not been approved for MDD.

Autism

Both risperidone and aripiprazole have received FDA labelling for autism.

Dementia and Alzheimer’s Disease

Between May 2007 and April 2008, Dementia and Alzheimer’s together accounted for 28% of atypical antipsychotic use in patients aged 65 or older. The FDA requires that all atypical antipsychotics carry a black box warning that the medication has been associated with an increased risk of mortality in elderly patients. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.

Adverse Effects

The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are widely believed to have a lower likelihood for the development of tardive dyskinesia than the typical antipsychotics. However, tardive dyskinesia typically develops after long-term (possibly decades) use of antipsychotics. It is not clear if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia.

Some of the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease. The research that Kabinoff et al. found that the increase in cardiovascular disease is seen regardless of the treatment they receive, instead it is caused by many different factors such as lifestyle or diet.

Sexual side effects have also been reported when taking atypical antipsychotics. In males antipsychotics reduce sexual interest, impair sexual performance with the main difficulties being failure to ejaculate. In females there may be abnormal menstrual cycles and infertility. In both males and females the breasts may become enlarged and a fluid will sometimes ooze from the nipples. Sexual adverse effects caused by some anti-psychotics are a result of an increase of prolactin. Sulpiride and Amisulpiride, as well as Risperdone and paliperidone (to a lesser extent) cause a high increase of prolactin.

In April 2005, the FDA issued an advisory and subsequent black box warning regarding the risks of atypical anti psychotic use among elderly patients with dementia. The FDA advisory was associated with decreases in the use of atypical antipsychotics, especially among elderly patients with dementia. Subsequent research reports confirmed the mortality risks associated with the use of both conventional and atypical antipsychotics to treat patients with dementia. Consequently, in 2008 the FDA issued although a black box warning for classical neuroleptics. Data on treatment efficacies are strongest for atypical antipsychotics. Adverse effects in patients with dementia include an increased risk of mortality and cerebrovascular events, as well as metabolic effects, extrapyramidal symptoms, falls, cognitive worsening, cardiac arrhythmia, and pneumonia. Conventional antipsychotics may pose an even greater safety risk. No clear efficacy evidence exists to support the use of alternative psychotropic classes (e.g. antidepressants, anticonvulsants).

Atypical antipsychotics may also cause anhedonia.

Drug-Induced OCD

Many different types of medication can create/induce pure OCD in patients that have never had symptoms before. A new chapter about OCD in the DSM-5 (2013) now specifically includes drug-induced OCD.

Atypical antipsychotics (second generation antipsychotics), such as olanzapine (Zyprexa), have been proven to induce de-novo OCD in patients.

Tardive Dyskinesia

All of the atypical antipsychotics warn about the possibility of tardive dyskinesia in their package inserts and in the PDR. It is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time to determine all of the long-term risks. One hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from D2 receptor and brain tissue. The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD.

Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% per year as opposed to the typicals at 5.5% per year.

Metabolism

Recently, metabolic concerns have been of grave concern to clinicians, patients and the FDA. In 2003, the FDA required all manufacturers of atypical antipsychotics to change their labelling to include a warning about the risks of hyperglycaemia and diabetes with atypical antipsychotics. It must also be pointed out that although all atypicals must carry the warning on their labelling, some evidence shows that atypicals are not equal in their effects on weight and insulin sensitivity. The general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased insulin sensitivity, followed by risperidone and quetiapine. Ziprasidone and aripiprazole are thought to have the smallest effects on weight and insulin resistance, but clinical experience with these newer agents is not as developed as that with the older agents. The mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs. Their effects on weight are believed to mostly derive from their actions on the H1 and 5-HT2C receptors, while their effects on insulin sensitivity are believed to be the result of a combination of their effects on body weight (as increased body mass is known to be a risk factor for insulin resistance) and their antagonistic effects on the M3receptor. Some of the newer agents, however, such as risperidone and its metabolite paliperidone, ziprasidone, lurasidone, aripiprazole, asenapine and iloperidone have clinically-insignificant effects on the M3 receptor and appear to carry a lower risk of insulin resistance. Whereas clozapine, olanzapine and quetiapine (indirectly via its active metabolite, norquetiapine) all antagonise the M3 receptor at therapeutic-relevant concentrations.

Recent evidence suggests a role of the α1 adrenoceptor and 5-HT2A receptor in the metabolic effects of atypical antipsychotics. The 5-HT2A receptor, however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics.

A study by Sernyak and colleagues found that the prevalence of diabetes in atypical antipsychotic treatments was statistically significantly higher than that of conventional treatment. The authors of this study suggest that it is a causal relationship the Kabinoff et al. suggest the findings only suggest a temporal association. Kabinoff et al. suggest that there is insufficient data from large studies to demonstrate a consistent or significant difference in the risk of insulin resistance during treatment with various atypical antipsychotics.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Pharmacodynamics

The atypical antipsychotics integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (D) receptors in order to effectively treat schizophrenia.

D2 Receptor: Hyperactive dopaminergic activity on D2 receptors in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an antipsychotic, antagonism of D2 receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D2 receptor antagonism throughout the entire dopamine pathway system. Unfortunately, it’s not possible to affect D2 receptors only in the mesolimbic pathway. Fortunately, 5-HT2A receptor antagonism reverses these side effects to some extent. Reducing D2 dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure, motivation, and the salience of one’s life experience. In the mesocortical pathway to the DLPFC and VMPFC, endogenous D2 receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D2 receptor antagonism here further compounds these problems. In the nigrostriatal pathway, D2 receptor antagonism results in extrapyramidal symptoms. If this antagonism occurs long enough, symptoms of EPS may become permanent, even if antipsychotic use is discontinued. In the tuberoinfundibular pathway, D2 receptor antagonism results in elevated prolactin. If prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralisation of bones, and possibly galactorrhea and amenorrhea.

5-HT2A Receptor: When serotonin is released on to postsynaptic 5-HT2A receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release. This brake is disrupted through action of a 5-HT2A antagonist, which disinhibits the dopamine neuron, stimulating dopamine release. The result of this is that dopamine competes with antipsychotic D2 antagonistic action at D2 receptors, thereby reducing antagonistic binding there and eliminating or lowering D2 antagonistic effects in several pathways of the dopamine system. In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation. Dopamine release in the mesolimbic pathway from 5-HT2A antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why atypical antipsychotics still retain part of their efficacy against the positive symptoms of schizophrenia through their D2 antagonism. When 5-HT2A antagonistic agent particles occupy 5-HT2A receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced. Furthermore, 5-HT2A receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic D2 receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia.

Some effects of 5-HT1A receptor activation include decreased aggressive behaviour/ideation, increased sociability, and decreased anxiety and depression. 5-HT2C activation blocks dopamine and inhibits norepinephrine release. Blockade of the 5-HT2C receptor increases serotonin, releasing norepinephrine and dopamine within the brain. But neuronal reuptake of norepinephrine is limited sharply by some antipsychotics, for example ziprasidone. Increased norepinephrine can cause increased glucose levels, which is to say blood sugar levels. Increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some antipsychotics if the norepinephrine is not inhibited. Inhibition of norepinephrine stabilises mood in humans. 5-HT6 receptor antagonists improve cognition, learning, and memory. The 5-HT7 receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The antipsychotics asenapine, lurasidone, risperidone, and aripiprazole are very potent at the 5-HT7 receptor. Antagonistic affinity for the H1 receptor also has an antidepressant effect. H1 antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels. However, the H1 receptor is linked to weight gain. To have partial agonism at the 5-HT1A receptor can yield absence of weight gain in an antipsychotic. This is very relevant for ziprasidone, but it creates a risk for a prolonged QTc interval. On the other hand, blockade of the 5-HT3 receptor removes the risk for a prolonged QTc interval, but then creates a larger risk for weight gain. Relation to the 5-HT3 receptor increases caloric uptake and glucose, which is seen in clozapine and olanzapine. Other ways for dopamine to resolve is to have agonism at both the D2 receptor and 5-HT1A receptor, which normalises the dopamine level in the brain. This occurs with haloperidol and aripiprazole.

Whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at D2 receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-HT2A antagonism, which is seen in atypical antipsychotics), or the positive mood, mood stabilisation, and cognitive improvement effect resulting from atypical antipsychotic serotonergic activity is greater for the overall quality of life effect of an atypical antipsychotic is a question that is variable between individual experience and the atypical antipsychotic(s) being used.

Terms

Inhibition. Disinhibition: The opposite process of inhibition, the turning on of a biological function. Release: Causes the appropriate neurotransmitters to be discharged in vesicles into the synapse where they attempt to bind to and activate a receptor. Downregulation and Upregulation.

Pharmacokinetics

Atypical antipsychotics are most commonly administered orally. Antipsychotics can also be injected, but this method is not as common. They are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood-brain barrier and placental barriers. Once in the brain, the antipsychotics work at the synapse by binding to the receptor. Antipsychotics are completely metabolised in the body and the metabolites are excreted in urine. These drugs have relatively long half-lives. Each drug has a different half-life, but the occupancy of the D2 receptor falls off within 24 hours with atypical antipsychotics, while lasting over 24 hours for the typical antipsychotics. This may explain why relapse into psychosis happens quicker with atypical antipsychotics than with typical antipsychotics, as the drug is excreted faster and is no longer working in the brain. Physical dependence with these drugs is very rare. However, if the drug is abruptly discontinued, psychotic symptoms, movement disorders, and sleep difficulty may be observed. It is possible that withdrawal is rarely seen because the AAP are stored in body fat tissues and slowly released.

Society and Culture

Between May 2007 and April 2008, 5.5 million Americans filled at least one prescription for an atypical antipsychotic. In patients under the age of 65, 71% of patients were prescribed an atypical antipsychotic to treat Schizophrenia or Bipolar Disorder where this dropped to 38% in patients aged 65 or above.