Clozapine
This medication is used to treat certain mental/mood disorders. Clozapine is a psychiatric medication that works by helping to restore the balance of certain natural substances in the brain. Clozapine decreases hallucinations and helps prevent suicide in people who are likely to try to harm themselves.
Is clozapine treatment-resistant schizophrenia?
Keywords: Treatment resistant schizophrenia, clozapine, barriers Clozapine use in schizophrenia Clozapine is the only medication licensed for treatment-resistant schizophrenia (TRS), which affects about one-third of those suffering from the disorder.
What is Clozaril (clozapine)?
What is Clozaril? Clozaril (clozapine) is an antipsychotic medicine. It works by changing the actions of chemicals in the brain. Clozaril is used to treat schizophrenia after other treatments have failed.
How does clozapine work in the brain?
Clozaril (clozapine) is an antipsychotic medication. It works by changing the actions of chemicals in the brain. Clozaril is used to treat severe schizophrenia, or to reduce the risk of suicidal behavior in people with schizophrenia or similar disorders.
What are the risks of taking Clozaril for schizophrenia?
There is a great risk for lowered white blood cell count and for seizures when taking Clozaril, which is why the medication is only prescribed when standard treatments for schizophrenia are not effective.
How does clozapine help schizophrenia?
Clozapine is an antipsychotic medicine that helps to adjust the levels of dopamine and other chemicals available in your brain. Clozapine reduces dopamine activity where it is too high, helping with symptoms like hallucinations.
What is the purpose of Clozaril?
This medication is used to treat certain mental/mood disorders (schizophrenia, schizoaffective disorders). Clozapine is a psychiatric medication (anti-psychotic type) that works by helping to restore the balance of certain natural substances (neurotransmitters) in the brain.
How does clozapine Clozaril work?
Clozapine is an anti-psychotic medication that works by blocking receptors in the brain for several neurotransmitters (chemicals that nerves use to communicate with each other) including dopamine type 4 receptors, serotonin type 2 receptors, norepinephrine receptors, acetylcholine receptors, and histamine receptors.
What is clozapine mechanism of action?
Mechanism of Action The mechanism by which clozapine exerts its effects involves the blocking of 5-HT2A/5-HT2C serotonin receptors and the D1-4 dopamine receptors, with the highest affinity for the D4 dopamine receptor.
Why is clozapine so effective?
Clozapine's relatively rapid dissociation from D2 receptors [13] and its antagonistic activity at the 5-HT2A receptors [11] have been put forward as mechanisms responsible for its effectiveness as an antipsychotic, and its actions at multiple receptors account for many of its adverse effects [14].
What is the difference between clozapine and Clozaril?
Clozaril (clozapine) is an antipsychotic medication that is used to treat severe schizophrenia symptoms in people who have not responded to other medications. Clozaril is also used to help reduce the risk of suicidal behavior in people with schizophrenia or similar disorders.
What does clozapine do to dopamine?
Clozapine produced significant and long-lasting increases in dopamine release in the principal sulcus, and to a lesser extent, in the caudate nucleus. Haloperidol did not produce a consistent effect on dopamine release in the principal sulcus, although it increased dopamine release in the caudate.
What can clozapine Clozaril cause?
SIDE EFFECTS: Drooling, drowsiness, dizziness, headache, shaking (tremor), vision problems (e.g., blurred vision), weight gain, and constipation may occur. Many of these effects (especially drowsiness) lessen as your body gets used to the medication.
How does clozapine work chemically?
The chemical structure of clozapine facilitates a relatively rapid dissociation from D2 receptors. After short-term occupation of D2 receptors, peak neural activity raises synaptic dopamine, which then displaces clozapine.
How is clozapine different from other antipsychotics?
Clozapine differs from conventional antipsychotics for its greater efficacy in controlling positive symptoms in people with treatment-resistant illness and by inducing few extra-pyramidal effects (Kane 1988, Wahlbeck 1999).
Which dopamine receptors does clozapine block?
Clozapine blocks dopamine, 5-HT2 and 5-HT3 responses in the medial prefrontal cortex: an in vivo microiontophoretic study. Eur Neuropsychopharmacol.
Does clozapine reduce dopamine?
Chronic treatment with clozapine selectively decreases basal dopamine release in nucleus accumbens but not in caudate-putamen as measured in vivo by brain microdialysis: further evidence for depolarization block.
Before Taking This Medicine
You should not take Clozaril if you have ever developed a severe infection or severe allergic reaction while taking this medicine.Clozaril is not a...
How Should I Take Clozaril?
Take Clozaril exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose...
What Happens If I Miss A Dose?
Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to...
What Should I Avoid While Taking Clozaril?
Clozaril can cause severe dizziness, slow heartbeats, fainting, or seizures. Do not take more of this medicine than recommended. Be careful if you...
Clozaril Dosing Information
Usual Adult Dose for Schizophrenia:Initial dose: 12.5 mg orally once or twice a dayTitration and Maintenance: May increase total daily dose in incr...
What Other Drugs Will Affect Clozaril?
Clozaril can cause a serious heart problem, especially if you use certain medicines at the same time. Tell your doctor about all medicines you use,...
What is clozapine used for?
Clozapine , a D (2)-5HT (2) antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death. Areas covered: The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of clozapine are covered in this article, ...
Is Clozapine the worst antipsychotic?
However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.
Is Clozapine good for schizophrenics?
Expert opinion: Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, ...
Is Clozapine a drug?
Clozapine , a D (2)-5HT (2) antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death.
Why is Clozaril prescribed?
Clozaril is also used to reduce the risk of suicidal behavior in people with schizophrenia or similar disorders.
How does Clozaril work?
It works by changing the actions of chemicals in the brain. Clozaril is used to treat schizophrenia after other treatments have failed. Clozaril is available only from a certified pharmacy under a special program.
What other drugs will affect Clozaril?
When you start or stop taking Clozaril, your doctor may need to adjust the doses of any other medicines you take on a regular basis.
How old do you have to be to take Clozaril?
Clozaril is not approved for use by anyone younger than 18 years old.
Can you take Clozapine with food?
You may take Clozaril with or without food . Clozapine affects your immune system and can have long lasting effects on your body. You may get infections more easily, even serious or fatal infections. You may need frequent medical tests while using this medicine and for a short time after your last dose.
Is Clozaril safe for dementia?
Clozaril is not approved for use in older adults with dementia -related psychosis.
Does Clozaril cause hives?
Clozaril side effects. Get emergency medical help if you have signs of an allergic reaction to Clozaril ( hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).
What is a schizophreniform disorder?
According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, schizophreniform disorder is a condition with symptoms similar to schizophrenia but lasting less than six months (DSM‐IV). In 1937 and 1939, follow‐up studies were undertaken on patients who initially presented with symptoms similar to schizophrenia. Two different outcomes were identified in those patients. One group, whose symptoms were typical of schizophrenia, were identified as having a poor prognosis. The other group, whose symptoms were similar to those of schizophrenia but who had prominent affective symptoms, had a better outcome; Langfeldt introduced the concept of schizophreniform psychoses to describe this latter group (Noreik 1967; Guldberg 1991). Langfeldt’s original schizophreniform cases were reviewed by other researchers using DSM‐III and International Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD‐9) criteria. They concluded that most of the original schizophreniform cases described by Langfeldt possibly appeared to more closely resemble affective disorders with psychoses, rather than schizophrenia‐like illness (Bergem 1990; Guldberg 1991). DSM‐IVuses schizophreniform disorder to define a disorder that would otherwise meet the diagnostic criteria for schizophrenia but lasts less than six months (Gelder 2001). There are currently no reliable data on prevalence rates of schizophreniform disorder (Kaplan 2005). Treatment is similar to that of schizophrenia. Good prognostic factors for schizophreniform illness include episodic illness, recurrent course and a family history of mood disorders (Benazzi 2003).
What is schizoaffective psychosis?
Schizoaffective psychosis can be considered as a syndrome on the continuum between schizophrenia and mood disorders (such as depression and bipolar affective disorder) and presents with symptoms of both these illnesses (Danileviciūte 2002). ICD‐10considers schizoaffective disorder as an episodic disorder in which both affective and schizophrenic symptoms are prominent but which does not justify a diagnosis of either schizophrenia or a depressive or manic episode. Studies on schizoaffective disorder suggest that it is relatively common in clinical settings. Among admissions to inpatient mental health facilities for functional psychosis, 10% to 30% comprise schizoaffective disorder. The lifetime prevalence of schizoaffective disorder is estimated to be between 0.5% and 0.8% and the illness typically presents with an episodic course (Azorin 2005). Psychotic features may include both positive and negative symptoms along with affective symptoms. Outcome is predicted by premorbid functioning, number of past episodes, persistence of psychotic features and degree of cognitive impairment. Vieta 2010suggests that bipolar‐type schizoaffective illness can be treated with second generation antipsychotics, either alone or in conjunction with a mood stabiliser. The depressive type of schizoaffective disorder can be treated with a second generation antipsychotic in conjunction with either an antidepressant or a mood stabiliser. Electroconvulsive therapy (ECT) can be considered in refractory cases. Prognosis appears to be better than for schizophrenia, but worse than for affective disorder (Azorin 2005).
How many people are affected by schizophrenia?
WHO 2013estimates that about 24 million people worldwide are affected by schizophrenia. The symptoms typically emerge in late adolescence or early adulthood. It is unclear as to what exactly causes schizophrenia, but both genetic and environmental factors are thought to play a role. WHO 2013identified a low incidence of 3 per 100,000, whereas McGrath 2008identified the median incidence of schizophrenia as 15.2 per 100,000 people. Saha 2005found no significant difference in prevalence between urban, rural, and mixed sites. The prevalence of schizophrenia in migrants is higher compared to native‐born individuals and is lower in poorer countries than in richer countries. Saha 2005identified the median point prevalence of schizophrenia (the proportion of people who suffer from schizophrenia at a specific point in time) as 4.6 per 1000; the median lifetime prevalence for persons (the number of people in the population who have ever manifested the disease) was 4.0 per 1000; and the lifetime morbid risk (the likelihood of a particular individual developing schizophrenia in their lifetime) as 7.2 per 1000. Acute schizophrenia predominantly manifests itself with positive symptoms such as abnormal experiences; these include abnormal perceptions in the absence of a stimulus (hallucinations), false fixed beliefs (delusions), and disordered thinking. Chronic schizophrenia typically manifests itself with negative symptoms. Though there is no complete agreement as to the specification of negative symptoms, it is generally agreed that they include poverty of speech, blunting of affect, lack of volition and social withdrawal (Gelder 2001). More than 50% of people with schizophrenia are not receiving appropriate care and about 90% of people with untreated schizophrenia live in developing countries (WHO 2013). Most cases of schizophrenia can be treated and those affected can lead a productive life and be integrated in society. The incidence of treatment resistance in schizophrenia is about 20% (Kerwin 2005). Clozapine reduces psychotic symptoms in 30% to 60% of such schizophrenia patients who have failed to respond to adequate trials of other antipsychotics (Buchanan 1995).
Is Clozapine good for schizophrenia?
Clozapine is useful in the treatment of schizophrenia and related disorders, particularly when other antipsychotic medications have failed. It improves positive symptoms (such as delusions and hallucinations) and negative symptoms (such as withdrawal and poverty of speech). However, it is unclear what dose of clozapine is most effective with the least side effects.
Is clozapine an antipsychotic?
Clozapine (Figure 1) was the first atypical antipsychotic to show definite benefit in treatment of patients where symptoms failed to respond to typical agents. Clozapine has the highest affinity for dopamine D4, 5‐HT1C, 5‐HT2, alpha 1, muscarinic and histamine H1 receptors, but moderate affinity is also seen for many other receptor subtypes (Coward 1992). Clozapine causes fewer extrapyramidal side effects (EPSEs) than typical antipsychotics (Kane 1988). Clozapine appears to be more active at the limbic site than the striatal site and this might explain its low extrapyramidal side effect profile. It is metabolized mainly in the liver. Norclozapine is an active metabolite of clozapine. Monitoring the plasma levels of clozapine and norclozapine helps to assess compliance. It is suggested that the therapeutic response is associated with clozapine blood levels between 200 ng/ml and 400 ng/ml (Kronig 1995). Chemicals that affect cytochrome enzymes can reduce or increase plasma clozapine concentration.
Does Clozapine affect mental health?
We found no evidence of effect on mental state between very low doses and standard doses of clozapine in terms of average BPRS‐A endpoint score (1 RCT, n = 31, MD 6.67, 95% CI −2.09 to 15.43, very low quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 58, MD 0.10, 95% CI −0.76 to 0.96, low‐quality evidence)
Is schizophrenia a mental illness?
Schizophrenia is a serious mental illness characterised by profound disruptions in thinking and speech, emotional processes, behaviour and sense of self (WHO 2013). It can have great impact in terms of both human suffering and societal expenditure (van Os 2009). It is among the world's top ten causes of long‐term disability, leading to problems in social and occupational functioning and self‐care (Meuser 2004). Before the introduction of clozapine, doctors largely relied on first generation (typical) antipsychotics, such as chlorpromazine, to control persisting symptoms and to prevent further exacerbations or relapse of illness (Kane 1990). Clozapine is the first second generation (atypical) antipsychotic drug introduced to the market. Arnt suggested that second generation antipsychotics are those that do not cause movement disorders (catalepsy) in rats at clinically effective doses (Arnt 1998). When clozapine was introduced it proved to be superior in controlling treatment‐resistant illness, with fewer extrapyramidal side effects (EPSEs) than typical antipsychotics such as chlorpromazine (Kane 1988). However, clozapine was largely withdrawn from use in 1975 following the death of some patients due to the development of agranulocytosis. This withdrawal, however, was not followed worldwide. For example, Scandinavia, Germany and China continued to use clozapine. Subsequent studies demonstrated that clozapine could be administered safely when patients are carefully monitored for side effects such as agranulocytosis (Kane 1988; Naheed 2001). Following this, clozapine was reintroduced in the USA in 1990 with hopes that it would improve quality of life, cognitive functioning and movement disorders, and also reduce negative symptoms such as poverty of speech, blunting of affect, lack of volition and social withdrawal in the management of treatment‐resistant schizophrenia. During this reintroduction, some safeguards were put in place; for example, clozapine is recommended to be used only in treatment‐resistant schizophrenia along with regular monitoring for side effects such as agranulocytosis.
Abstract
Early and effective treatment in first-episode schizophrenia is associated with better outcomes. Evidence suggests that response is generally robust in a first antipsychotic trial, but a marked reduction in response rate is observed among patients for whom a second trial is warranted, and even further reductions are seen in subsequent trials.
Clozapine and Current Treatment Algorithms
Despite the introduction of a number of newer atypical antipsychotics over the past two decades, clozapine remains the treatment of choice in refractory schizophrenia, a position endorsed by various guidelines ( 4 – 7 ).
Treatment Response in Early Schizophrenia
Schizophrenia is characterized by a differential response to antipsychotic treatment based on stage of illness, with evidence that shorter duration of untreated psychosis is associated with greater antipsychotic response ( 14 ).
Clozapine as First-Line Treatment in Schizophrenia
Only four published trials have examined the use of clozapine as first-line treatment. An open 12-week trial (N=30) in China evaluating clozapine in first-episode schizophrenia found it to be both efficacious and safe, leading to the conclusion that clozapine should be used in this population ( 34 ).
Interpreting the Evidence
It is critical that the available data be interpreted correctly. In one open trial, clozapine was found to be safe and efficacious ( 34 ). In another, a cumulative response rate of 66.4% was calculated for clozapine ( 37 ), comparable to a previously reported rate for fluphenazine ( 38 ).
Conclusions and Recommendations
Research has approached the issue of clozapine as first-line treatment in schizophrenia from two perspectives. The first addresses whether longer-term outcome is influenced differentially by use of clozapine as first-line treatment compared with other antipsychotics. The evidence gathered to date, albeit limited, suggests that this is not the case.
How long should clozapine be used?
1It has been proposed that duration of clozapine trials should be 2 mo for patients with aggression or self- harm, 3 mo for those with positive symptoms, and 4 mo for those with negative and cognitive symptoms[13].
How many people develop clozapine resistance?
Core Tip: About 40%-70% of patients develop clozapine-resistant schizophrenia, which has serious health, economic, and social consequences. Research on clozapine-resistant schizophrenia has provided little support for the efficacy of psychotropics, electroconvulsive therapy, and cognitive-behavioural therapy in augmenting clozapine non-response. Therefore, newer approaches are needed including a clinical consensus about using the most effective of the currently available augmentation strategies. Augmentation with long-acting antipsychotic injections or multi-component psychosocial interventions could also be tried. Finally, the best option at present may be to prevent clozapine resistance from developing by optimizing clozapine treatment and collaborating with patients and caregivers to ensure its continuation.
How many RCTs are there for clozapine augmentation?
31 RCTs and quasi-RCTs of augmentation with SGAs (n= 26) and FGAs (n = 5) including clozapine augmentation.
What is the best treatment for CRS?
In routine clinical practice, the commonest strategy to deal with CRS is augmentation with another antipsychotic[9,11,20,21]. Mood stabilizer or antidepressant augmentation is used less frequently. Some treatment guidelines also endorse augmentation with antipsychotics[13]. Over the past 25 years, many trials of clozapine augmentation with medications and other treatments have been conducted. Additionally, more than 50 reviews on the subject including narrative and systematic reviews, individual meta-analyses, and reviews of different meta-analyses have been published.
How many meta analyses of FGA and SGA augmentation of clozapine?
14 meta-analyses of FGA and SGA augmentation of clozapine.
Is clozapine monotherapy the same as clozapine?
Clozapine combinations no different from clozapine monotherapy for negative symptoms.