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Clozapine

Clozapine is a psychiatric medication and was the first atypical antipsychotic (also called second-generation antipsychotic) to be discovered. It is primarily used to treat people with schizophrenia and schizoaffective disorder who have had an inadequate response to two 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 recommended by multiple international treatment guidelines, after resistance to two other antipsychotic medications, and is the only treatment likely to result in improvement if two (or one ) other antipsychotic has not had a satisfactory effect. Long term follow-up studies from Finland show significant improvements in terms of overall mortality including from suicide and all causes. Clozapine is on the World Health Organization's List of Essential Medicines. It is available as a generic medication and so it is not usually promoted by pharmaceutical companies. 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. Potential adverse effects include agranulocytosis, seizures, myocarditis (inflammation of the heart), hyperglycemia (high blood glucose levels), and 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.

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 variant in the region. Whilst the drug continued to be manufactured by Sandoz, and remained available in Europe, development in the U.S. 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 behavior. 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 Risk Evaluation and Mitigation Strategy (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). Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).

Schizophrenia
The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark multicenter double blind study in which clozapine (up to 900 mg/d) showed marked benefits compared to chlorpromazine (up to 1800 mg/d) in a group of patients with protracted psychosis who had already shown an inadequate response to at least three previous antipsychotics including a prior single blind trial of haloperidol (mean 61+/− 14 mg/d for six weeks). 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 hospitalization. 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.

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 for individuals in whom two other antipsychotics have already been tried, evidence indicates that clozapine might instead be used as a second line drug. Clozapine treatment has been demonstrated to produce 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. A long term follow-up study showed efficacy in terms of both psychiatric and somatic hospitialisation, but with bipolar disorder this effect was not as strong as with some other treatments (olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37–0.80), haloperidol LAI (aHR = 0.62, 0.47–0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52–0.85), lithium (aHR = 0.74, 95% CI 0.71–0.76) and clozapine (aHR = 0.75, 95% CI 0.64–0.87)). Bipolar disorder is an off-label 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 off-label.

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 pre-clozapine 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, a CK level may also be drawn.

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 temperature. Since orthostatic hypotension can be problematic, blood pressure should be monitored both sitting and standing. If there is a significant drop then the rate of the dose increase may be slowed.

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, overestimated the incidence of side effects, and did not appreciate that many patients prefer to take clozapine over 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. 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.

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, such as retrograde ejaculation and priapism, have been reported while taking clozapine. Rare adverse effects include periorbital edema. Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.

Neutropenia and agranulocytosis
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 usually reserved for people who have not responded to at least 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 blood 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 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 U.S. has been lower than those currently used in the U.K. 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 7700 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 1000 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 shown success in over 60% of reported cases.

Gastrointestinal hypomotility
Another underrecognized and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal 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 preemptive 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, paresthesia, 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-recognized. This side-effect may be amendable to bethanechol.

Withdrawal effects
Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhea, 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 hyperglycemia, 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. For people who gain weight because of clozapine, taking metformin may reportedly improve three of the five components of the metabolic syndrome: waist circumference, fasting glucose, and fasting triglycerides.

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 or the 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.

Pharmacodynamics
Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors. It acts as an antagonist at both receptors.

Clozapine is an inverse agonist at the 5-HT2A subtype 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 feces. 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.

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.

title: Clozapine


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Psychosurgery

Psychosurgery, also called neurosurgery for mental disorder (NMD), is the neurosurgical treatment of mental disorders. Psychosurgery has always been a controversial medical field. The modern history of psychosurgery begins in the 1880s under the Swiss psychiatrist Gottlieb Burckhardt. The first significant foray into psychosurgery in the 20th century was conducted by the Portuguese neurologist Egas Moniz who, during the mid-1930s, developed the operation known as leucotomy. The practice was enthusiastically taken up in the United States by the neuropsychiatrist Walter Freeman and the neurosurgeon James W. Watts who devised what became the standard prefrontal procedure and named their operative technique lobotomy, although the operation was called leucotomy in the United Kingdom. In spite of the award of the Nobel prize to Moniz in 1949, the use of psychosurgery declined during the 1950s. By the 1970s the standard Freeman-Watts type of operation was very rare, but other forms of psychosurgery, although used on a much smaller scale, survived. Some countries have abandoned psychosurgery altogether; in others, for example the US and the UK, it is only used in a few centres on small numbers of people with depression or obsessive-compulsive disorder (OCD). In some countries it is also used in the treatment of schizophrenia and other disorders.

Psychosurgery is a collaboration between psychiatrists and neurosurgeons. During the operation, which is carried out under a general anaesthetic and using stereotactic methods, a small piece of brain is destroyed or removed. The most common types of psychosurgery in current or recent use are anterior capsulotomy, cingulotomy, subcaudate tractotomy and limbic leucotomy. Lesions are made by radiation, thermo-coagulation, freezing or cutting. About a third of patients show significant improvement in their symptoms after operation. Advances in surgical technique have greatly reduced the incidence of death and serious damage from psychosurgery; the remaining risks include seizures, incontinence, decreased drive and initiative, weight gain, and cognitive and affective problems.

Currently, interest in the neurosurgical treatment of mental illness is shifting from ablative psychosurgery (where the aim is to destroy brain tissue) to deep brain stimulation (DBS) where the aim is to stimulate areas of the brain with implanted electrodes.

Medical uses
All the forms of psychosurgery in use today (or used in recent years) target the limbic system, which involves structures such as the amygdala, hippocampus, certain thalamic and hypothalamic nuclei, prefrontal and orbitofrontal cortex, and cingulate gyrus—all connected by fibre pathways and thought to play a part in the regulation of emotion. There is no international consensus on the best target site.

Anterior cingulotomy was first used by Hugh Cairns in the UK, and developed in the US by H.T. Ballantine Jr. In recent decades it has been the most commonly used psychosurgical procedure in the US. The target site is the anterior cingulate cortex; the operation disconnects the thalamic and posterior frontal regions and damages the anterior cingulate region.

Anterior capsulotomy was developed in Sweden, where it became the most frequently used procedure. It is also used in Scotland and Canada. The aim of the operation is to disconnect the orbitofrontal cortex and thalamic nuclei by inducing a lesion in the anterior limb of internal capsule.

Subcaudate tractotomy was the most commonly used form of psychosurgery in the UK from the 1960s to the 1990s. It targets the lower medial quadrant of the frontal lobes, severing connections between the limbic system and supra-orbital part of the frontal lobe.

Limbic leucotomy is a combination of subcaudate tractotomy and anterior cingulotomy. It was used at Atkinson Morley Hospital London in the 1990s and also at Massachusetts General Hospital.

Amygdalotomy, which targets the amygdala, was developed as a treatment for aggression by Hideki Narabayashi in 1961 and is still used occasionally, for example at the Medical College of Georgia.

There is debate about whether deep brain stimulation (DBS) should be classed as a form of psychosurgery.

Effectiveness
Success rates for anterior capsulotomy, anterior cingulotomy, subcaudate tractotomy, and limbic leucotomy in treating depression and OCD have been reported as between 25 and 70 percent. The quality of outcome data is poor and the Royal College of Psychiatrists in their 2000 report concluded that there were no simple answers to the question of modern psychosurgery's clinical effectiveness; studies suggested improvements in symptoms following surgery but it was impossible to establish the extent to which other factors contributed to this improvement. Research into the effects of psychosurgery has not been able to overcome a number of methodological problems, including the problems associated with non-standardised diagnoses and outcome measurements, the small numbers treated at any one centre, and positive publication bias. Controlled studies are very few in number and there have been no placebo-controlled studies. There are no systematic reviews or meta-analyses.

Modern techniques have greatly reduced the risks of psychosurgery, although risks of adverse effects still remain. Whilst the risk of death or vascular injury has become extremely small, there remains a risk of seizures, fatigue, and personality changes following operation.

A 2012 follow-up study of eight depressed patients who underwent anterior capsulotomy in Vancouver, Canada, classified five of them as responders at two to three years after surgery. Results on neuropsychological testing were unchanged or improved, although there were isolated deficits and one patient was left with long-term frontal psychobehavioral changes and fatigue. One patient, aged 75, was left mute and akinetic for a month following surgery and then developed dementia.

China
In China, psychosurgical operations which make a lesion in the nucleus accumbens are used in the treatment of drug and alcohol dependence. Psychosurgery is also used in the treatment of schizophrenia, depression, and other mental disorders. Psychosurgery is not regulated in China, and its use has been criticised in the West.

India
India had an extensive psychosurgery programme until the 1980s, using it to treat addiction, and aggressive behaviour in adults and children, as well as depression and OCD. Cingulotomy and capsulotomy for depression and OCD continue to be used, for example at the BSES MG Hospital in Mumbai.

Japan
In Japan the first lobotomy was performed in 1939 and the operation was used extensively in mental hospitals. However, psychosurgery fell into disrepute in the 1970s, partly due to its use on children with behavioural problems.

Australia and New Zealand
In the 1980s there were 10–20 operations a year in Australia and New Zealand. The number had decreased to one or two a year by the 1990s. In Victoria, there were no operations between 2001 and 2006, but between 2007 and 2012 the Victoria Psychosurgery Review Board dealt with 12 applications, all them for DBS.

Europe
In the 20-year period 1971–1991 the Committee on Psychosurgery in the Netherlands and Belgium oversaw 79 operations. Since 2000 there has been only one centre in Belgium performing psychosurgery, carrying out about 8 or 9 operations a year (some capsulotomies and some DBS), mostly for OCD.

In France about five people a year were undergoing psychosurgery in the early 1980s. In 2005 the Health Authority recommended the use of ablative psychosurgery and DBS for OCD.

In the early 2000s in Spain about 24 psychosurgical operations (capsulotomy, cingulotomy, subcaudate tractotomy, and hypothalamotomy) a year were being performed. OCD was the most common diagnosis, but psychosurgery was also being used in the treatment of anxiety and schizophrenia, and other disorders.

In the UK between the late 1990s and 2009 there were just two centres using psychosurgery: a few stereotactic anterior capsulotomies are performed every year at the University Hospital of Wales, Cardiff, while anterior cingulotomies are carried out by the Advanced Interventions Service at Ninewells Hospital, Dundee. The patients have diagnoses of depression, obsessive-compulsive disorder, and anxiety. Ablative psychosurgery was not performed in England between the late 1990s and 2009, although a couple of hospitals have been experimenting with DBS. In 2010, Frenchay Hospital in Bristol performed an anterior cingulotomy on a woman who had previously undergone DBS.

In Russia in 1998 the Institute of the Human Brain (Russian Academy of Sciences) started a programme of stereotactic cingulotomy for the treatment of drug addiction. About 85 people, all under the age of 35, were operated on annually. In the Soviet Union, leucotomies were used for the treatment of schizophrenia in the 1940s, but the practice was prohibited by the Ministry of Health in 1950.

North America
In the United States, the Massachusetts General Hospital has a psychosurgery program. Operations are also performed at a few other centres.

In Mexico, psychosurgery is used in the treatment of anorexia and aggression.

In Canada, anterior capsulotomies are used in the treatment of depression and OCD.

South America
Venezuela has three centres performing psychosurgery. Capsulotomies, cingulotomies and amygdalotomies are used to treat OCD and aggression.

Early psychosurgery
Evidence of trepanning (or trephining)—the practice of drilling holes in the skull—has been found in a skull from a Neolithic burial site in France, dated to about 5100 BC although it was also used to treat brain cranial trauma. There have also been archaeological finds in South America, while in Europe trepanation was carried out in classical and medieval times. The first systematic attempt at psychosurgery is commonly attributed to the Swiss psychiatrist Gottlieb Burckhardt. In December 1888 Burckhardt operated on the brains of six patients (one of whom died a few days after the operation) at the Préfargier Asylum, cutting out a piece of cerebral cortex. He presented the results at the Berlin Medical Congress and published a report, but the response was hostile and he did no further operations. Early in the 20th century, Russian neurologist Vladimir Bekhterev and Estonian neurosurgeon Ludvig Puusepp operated on three patients with mental illness, with discouraging results.

1930s–1950s
Although there had been earlier attempts to treat psychiatric disorders with brain surgery, it was Portuguese neurologist Egas Moniz who was responsible for introducing the operation into mainstream psychiatric practice. He also coined the term psychosurgery. Moniz developed a theory that people with mental illnesses, particularly "obsessive and melancholic cases", had a disorder of the synapses which allowed unhealthy thoughts to circulate continuously in their brains. Moniz hoped that by surgically interrupting pathways in their brain he could encourage new healthier synaptic connections. In November 1935, under Moniz's direction, surgeon Pedro Almeida Lima drilled a series of holes on either side of a woman's skull and injected ethanol to destroy small areas of subcortical white matter in the frontal lobes. After a few operations using ethanol, Moniz and Almeida Lima changed their technique and cut out small cores of brain tissue. They designed an instrument which they called a leucotome and called the operation a leucotomy (cutting of the white matter). After twenty operations, they published an account of their work. The reception was generally not friendly but a few psychiatrists, notably in Italy and the US, were inspired to experiment for themselves.

In the US, psychosurgery was taken up and zealously promoted by neurologist Walter Freeman and neurosurgeon James Watts. They started a psychosurgery program at George Washington University in 1936, first using Moniz's method but then devised a method of their own in which the connections between the prefrontal lobes and deeper structures in the brain were severed by making a sweeping cut through a burr hole on either side of the skull. They called their new operation a lobotomy.

Freeman went on to develop a new form of lobotomy which dispensed with the need for a neurosurgeon. He hammered an ice pick-like instrument, an orbitoclast, through the eye socket and swept through the frontal lobes. The transorbital or "ice pick" lobotomy was done under local anesthesia or using electroconvulsive therapy to render the patient unconscious and could be performed in mental hospitals lacking surgical facilities. Such was Freeman's zeal that he began to travel around the nation in his own personal van, which he called his "lobotomobile", demonstrating the procedure in psychiatric hospitals. Freeman's patients included 19 children, one of whom was 4 years old.

The 1940s saw a rapid expansion of psychosurgery, in spite of the fact that it involved a significant risk of death and severe personality changes. By the end of the decade, up to 5000 psychosurgical operations were being carried out annually in the US. In 1949, Moniz was awarded the Nobel Prize for Physiology or Medicine.

Beginning in the 1940s various new techniques were designed in the hope of reducing the adverse effects of the operation. These techniques included William Beecher Scoville's orbital undercutting, Jean Talairach's anterior capsulotomy, and Hugh Cairn's bilateral cingulotomy. Stereotactic techniques made it possible to place lesions more accurately, and experiments were done with alternatives to cutting instruments such as radiation. Psychosurgery nevertheless went into rapid decline in the 1950s, due to the introduction of new drugs and a growing awareness of the long-term damage caused by the operations, as well as doubts about its efficacy. By the 1970s, the standard or transorbital lobotomy had been replaced with other forms of psychosurgical operations.

1960s to the present
During the 1960s and 1970s, psychosurgery became the subject of increasing public concern and debate, culminating in the US with congressional hearings. Particularly controversial in the United States was the work of Harvard neurosurgeon Vernon Mark and psychiatrist Frank Ervin, who carried out amygdalotomies in the hope of reducing violence and "pathologic aggression" in patients with temporal lobe seizures and wrote a book entitled Violence and the Brain in 1970. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1977 endorsed the continued limited use of psychosurgical procedures. Since then, a few facilities in some countries, such as the US, have continued to use psychosurgery on small numbers of patients. In the US and other Western countries, the number of operations has further declined over the past 30 years, a period during which there had been no major advances in ablative psychosurgery.

Ethics
Psychosurgery has a controversial history, and despite modifications, still raises serious questions about benefit, risks, and the adequacy with which consent is obtained. Its continued use is defended by references to the "therapeutic imperative" to do something in the case of psychiatric patients who have not responded to other forms of treatment, and the evidence that some patients see improvement in their symptoms following surgery. There remain however problems concerning the rationale, indications and efficacy of psychosurgery, and the results of the operation raise questions of "identity, spirit, relationships, integrity and human flourishing".

Individuals who underwent psychosurgery

 * Lena Zavaroni (1963–1999), Scottish child star and singer who had suffered from anorexia and depression for many years, underwent a stereotactic anterior capsulotomy at the University of Wales Hospital in Cardiff in 1999. She died of pneumonia three weeks later.
 * Josef Hassid: Polish violin prodigy who died at 26 following psychosurgery.
 * Rosemary Kennedy: Walter Freeman's most famous patient and sister of President John F. Kennedy. She was left with permanent mental incapacity as a result of the procedure, unable to speak or walk.
 * Rose Williams: Sister of Tennessee Williams.
 * Howard Dully: One of Walter Freeman's youngest patients, author of My Lobotomy (2007).

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Psychosurgery


text:
Dalton

Dalton may refer to:

Science

 * Dalton (crater), a lunar crater
 * Dalton (program), chemistry software
 * Dalton (unit) (Da), the atomic mass unit
 * John Dalton, chemist, physicist and meteorologist
 * 12292 Dalton, an asteroid

Entertainment

 * Dalton (Buffyverse), minor character from Buffy the Vampire Slayer television series
 * Dalton (band), Danish musical band
 * Dalton (Chrono Trigger), non-playable main character in Chrono Trigger
 * The Dalton Brothers (band), a parodistic country band created by U2
 * The Daltons (Lucky Luke), fictional outlaws in Lucky Luke comic book series
 * Dalton Academy, a fictional school in the TV series Glee
 * Dalton Russell, character played by Clive Owen in 2006 film Inside Man
 * The Daltons (2010 TV series), a French animated TV series

United Kingdom

 * Dalton-le-Dale, County Durham, England
 * Dalton-in-Furness, Cumbria (historically in Lancashire), England
 * Dalton, Cumbria, near Burton-in-Kendal (historically in Lancashire), England
 * Dalton, Dumfries and Galloway, Scotland
 * Dalton, Hambleton, North Yorkshire, England
 * Dalton, Hexhamshire, a location in Northumberland, England
 * Dalton, Lancashire, near Skelmersdale, England
 * Dalton, Richmondshire, North Yorkshire, England
 * Dalton, South Lanarkshire, a location in Scotland
 * Dalton, South Yorkshire, England
 * Dalton, Stamfordham, a location in Northumberland, England
 * Dalton, West Yorkshire, England

United States

 * Dalton, Georgia
 * Dalton Gardens, Idaho
 * Dalton City, Illinois
 * Dalton, Indiana
 * Dalton Township, Wayne County, Indiana
 * Dalton, Kansas
 * Dalton, Massachusetts
 * Dalton Township, Michigan
 * Dalton, Minnesota
 * Dalton, Missouri
 * Dalton, Nebraska
 * Dalton, New Hampshire
 * Dalton, New York
 * Dalton, North Carolina
 * Dalton, Ohio
 * Dalton, Pennsylvania
 * Dalton Creek, a stream in Utah
 * Dalton, Wisconsin

Elsewhere

 * Dalton, Algoma District, Ontario
 * Dalton Township, Ontario
 * Dalton, Israel
 * Dalton, KwaZulu-Natal, South Africa
 * Dalton, New South Wales, Australia

Transportation

 * Dalton Airport (Michigan) in Flushing, Michigan, United States
 * Dalton Municipal Airport in Dalton, Georgia
 * Dalton Highway, in Alaska, United States
 * Dalton Trail, a trail between Alaska and Canada
 * Dalton station (Ontario), in Canada
 * Dalton railway station, in Cumbria, England

Other uses

 * Dalton (given name)
 * Dalton (surname)
 * Dalton Gang, American Old West outlaws
 * Dalton Armoury, Scarborough, Ontario, a Canadian Forces facility
 * Dalton Barracks, Royal Air Force station near Abingdon, Oxfordshire
 * Dalton Castle, Cumbria, in Dalton-in-Furness, Cumbria, England
 * Dalton Plan, an educational concept created by Helen Parkhurst
 * Dalton School, a private school in New York City
 * Dalton State College, one of eight state colleges in the University System of Georgia
 * Dalton tradition, a distinctive shape of stone arrowhead
 * Dalton Winery, a winery in Israel
 * Four Seasons Hotel & Private Residences, One Dalton Street

title: Dalton


text:
Calorimeter

A calorimeter is a device used for calorimetry, or the process of measuring the heat of chemical reactions or physical changes as well as heat capacity. Differential scanning calorimeters, isothermal micro calorimeters, titration calorimeters and accelerated rate calorimeters are among the most common types. A simple calorimeter just consists of a thermometer attached to a metal container full of water suspended above a combustion chamber. It is one of the measurement devices used in the study of thermodynamics, chemistry, and biochemistry.

To find the enthalpy change per mole of a substance A in a reaction between two substances A and B, the substances are separately added to a calorimeter and the initial and final temperatures (before the reaction has started and after it has finished) are noted. Multiplying the temperature change by the mass and specific heat capacities of the substances gives a value for the energy given off or absorbed during the reaction. Dividing the energy change by how many moles of A were present gives its enthalpy change of reaction.

$$q = C_\text{v}(T_f - T_i)$$ where $q$ is the amount of heat according to the change in temperature measured in joules and $C_{v}$ is the heat capacity of the calorimeter which is a value associated with each individual apparatus in units of energy per temperature (joules/kelvin).

History
In 1761 Joseph Black introduced the idea of latent heat which led to the creation of the first ice calorimeters. In 1780, Antoine Lavoisier used the heat from the guinea pig's respiration to melt snow surrounding his apparatus, showing that respiratory gas exchange is combustion, similar to a candle burning. Lavoisier dubbed this apparatus the calorimeter, based on both Greek and Latin roots. One of the first ice calorimeters was used in the winter of 1782 by Lavoisier and Pierre-Simon Laplace, which relied on the heat required to melt ice to water to measure the heat released from chemical reactions.

Adiabatic calorimeters
An adiabatic calorimeter is a calorimeter used to examine a runaway reaction. Since the calorimeter runs in an adiabatic environment, any heat generated by the material sample under test causes the sample to increase in temperature, thus fueling the reaction.

No adiabatic calorimeter is fully adiabatic - some heat will be lost by the sample to the sample holder. A mathematical correction factor, known as the phi-factor, can be used to adjust the calorimetric result to account for these heat losses. The phi-factor is the ratio of the thermal mass of the sample and sample holder to the thermal mass of the sample alone.

Reaction calorimeters
A reaction calorimeter is a calorimeter in which a chemical reaction is initiated within a closed insulated container. Reaction heats are measured and the total heat is obtained by integrating heatflow versus time. This is the standard used in industry to measure heats since industrial processes are engineered to run at constant temperatures. Reaction calorimetry can also be used to determine maximum heat release rate for chemical process engineering and for tracking the global kinetics of reactions. There are four main methods for measuring the heat in reaction calorimeter:

Heat flow calorimeter
The cooling/heating jacket controls either the temperature of the process or the temperature of the jacket. Heat is measured by monitoring the temperature difference between heat transfer fluid and the process fluid. In addition, fill volumes (i.e. wetted area), specific heat, heat transfer coefficient have to be determined to arrive at a correct value. It is possible with this type of calorimeter to do reactions at reflux, although it is very less accurate.

Heat balance calorimeter
The cooling/heating jacket controls the temperature of the process. Heat is measured by monitoring the heat gained or lost by the heat transfer fluid.

Power compensation
Power compensation uses a heater placed within the vessel to maintain a constant temperature. The energy supplied to this heater can be varied as reactions require and the calorimetry signal is purely derived from this electrical power.

Constant flux
Constant flux calorimetry (or COFLUX as it is often termed) is derived from heat balance calorimetry and uses specialized control mechanisms to maintain a constant heat flow (or flux) across the vessel wall.

Bomb calorimeters

A bomb calorimeter is a type of constant-volume calorimeter used in measuring the heat of combustion of a particular reaction. Bomb calorimeters have to withstand the large pressure within the calorimeter as the reaction is being measured. Electrical energy is used to ignite the fuel; as the fuel is burning, it will heat up the surrounding air, which expands and escapes through a tube that leads the air out of the calorimeter. When the air is escaping through the copper tube it will also heat up the water outside the tube. The change in temperature of the water allows for calculating calorie content of the fuel.

In more recent calorimeter designs, the whole bomb, pressurized with excess pure oxygen (typically at 30 atm) and containing a weighed mass of a sample (typically 1–1.5 g) and a small fixed amount of water (to saturate the internal atmosphere, thus ensuring that all water produced is liquid, and removing the need to include enthalpy of vaporization in calculations), is submerged under a known volume of water (ca. 2000 ml) before the charge is electrically ignited. The bomb, with the known mass of the sample and oxygen, form a closed system — no gases escape during the reaction. The weighed reactant put inside the steel container is then ignited. Energy is released by the combustion and heat flow from this crosses the stainless steel wall, thus raising the temperature of the steel bomb, its contents, and the surrounding water jacket. The temperature change in the water is then accurately measured with a thermometer. This reading, along with a bomb factor (which is dependent on the heat capacity of the metal bomb parts), is used to calculate the energy given out by the sample burn. A small correction is made to account for the electrical energy input, the burning fuse, and acid production (by titration of the residual liquid). After the temperature rise has been measured, the excess pressure in the bomb is released.

At its core, a bomb calorimeter consists of a small cup to contain the sample, oxygen, a stainless steel bomb, water, a stirrer, a thermometer, the dewar or insulating container (to prevent heat flow from the calorimeter to the surroundings) and an ignition circuit connected to the bomb. By using stainless steel for the bomb, the reaction will occur with no volume change observed.

Since there is no heat exchange between the calorimeter and surroundings (Q = 0) (adiabatic), no work is performed (W = 0)

Thus, the total internal energy change

 * $$\Delta E_\text{total} = Q + W = 0$$

Also, total internal energy change

 * $$\Delta E_\text{total} = \Delta E_\text{system} + \Delta E_\text{surroundings} = 0$$
 * $$\Delta E_\text{system} = -\Delta E_\text{surroundings} = -C_\text{v} \Delta T$$
 * (constant volume $$\mathrm{d}V = 0$$)

where $$C_\text{v}$$ is heat capacity of the bomb

Before the bomb can be used to determine heat of combustion of any compound, it must be calibrated. The value of $$C_\text{v}$$ can be estimated by
 * $$C_\text{v(calorimeter)} = m_\text{water} C_\text{v(water)} + m_\text{steel} C_\text{v(steel)}$$
 * $$m_\text{water}$$ and $$m_\text{steel}$$ can be measured;
 * $$C_\text{v(water)} = 1 \text{ cal g}^{-1} \text{ K}^{-1}$$
 * $$C_\text{v(steel)} = 0.1 \text{ cal g}^{-1} \text{ K}^{-1}$$

In the laboratory, $$C_\text{v}$$ is determined by running a compound with known heat of combustion value: $$C_\text{v} = {H_\text{c} \over \Delta T}$$

Common compounds are benzoic acid ($$H_\text{c} = 6318 \text{ cal/g}$$) or p-methyl benzoic acid ($$H_\text{c} = 6957 \text{ cal/g}$$).

Temperature ($T$) is recorded every minute and $$\Delta T = T_\text{final} - T_\text{initial}$$

A small factor contributes to the correction of the total heat of combustion is the fuse wire. Nickel fuse wire is often used and has heat of combustion: 981.2cal/g.

In order to calibrate the bomb, a small amount (~ 1g) of benzoic acid, or p-methyl benzoic acid is weighed. A length of nickel fuse wire (~10 cm) is weighed both before and after the combustion process. Mass of fuse wire burned $$\Delta m = m_\text{before} - m_\text{after}$$

The combustion of sample (benzoic acid) inside the bomb
 * $$\Delta H_\text{c} = C_\text{v} \Delta T\ \rightarrow C_\text{v} = {\Delta H_\text{c} \over \Delta T}$$
 * $$\Delta H_\text{c} = C_\text{v} \Delta T\ \rightarrow C_\text{v} = {\Delta H_\text{c} \over \Delta T}$$

Once $$C_\text{v}$$ value of the bomb is determined, the bomb is ready to use to calculate heat of combustion of any compounds by
 * $$\Delta H_\text{c} = C_\text{v} \Delta T$$

Combustion of non-flammables
The higher pressure and concentration of in the bomb system can render combustible some compounds that are not normally flammable. Some substances do not combust completely, making the calculations harder as the remaining mass has to be taken into consideration, making the possible error considerably larger and compromising the data.

When working with compounds that are not as flammable (that might not combust completely) one solution would be to mix the compound with some flammable compounds with a known heat of combustion and make a pallet with the mixture. Once the $C_\text{v}$ of the bomb is known, the heat of combustion of the flammable compound ($C_{FC}$), of the wire ($C_{W}$) and the masses ($m_{FC}$ and $m_{W}$), and the temperature change (ΔT), the heat of combustion of the less flammable compound ($C_{LFC}$) can be calculated with:

 * CLFC = Cv ΔT − CFC mFC − CW mW

Calvet-type calorimeters
The detection is based on a three-dimensional fluxmeter sensor. The fluxmeter element consists of a ring of several thermocouples in series. The corresponding thermopile of high thermal conductivity surrounds the experimental space within the calorimetric block. The radial arrangement of the thermopiles guarantees an almost complete integration of the heat. This is verified by the calculation of the efficiency ratio that indicates that an average value of 94% ± 1% of heat is transmitted through the sensor on the full range of temperature of the Calvet-type calorimeter. In this setup, the sensitivity of the calorimeter is not affected by the crucible, the type of purgegas, or the flow rate. The main advantage of the setup is the increase of the experimental vessel's size and consequently the size of the sample, without affecting the accuracy of the calorimetric measurement.

The calibration of the calorimetric detectors is a key parameter and has to be performed very carefully. For Calvet-type calorimeters, a specific calibration, so called Joule effect or electrical calibration, has been developed to overcome all the problems encountered by a calibration done with standard materials. The main advantages of this type of calibration are as follows:
 * It is an absolute calibration.
 * The use of standard materials for calibration is not necessary. The calibration can be performed at a constant temperature, in the heating mode and in the cooling mode.
 * It can be applied to any experimental vessel volume.
 * It is a very accurate calibration.

An example of Calvet-type calorimeter is the C80 Calorimeter (reaction, isothermal and scanning calorimeter).

Adiabatic and Isoperibol calorimeters
Sometimes referred to as constant-pressure calorimeters, adiabatic calorimeters measure the change in enthalpy of a reaction occurring in solution during which the no heat exchange with the surroundings is allowed (adiabatic) and the atmospheric pressure remains constant.

An example is a coffee-cup calorimeter, which is constructed from two nested Styrofoam cups, providing insulation from the surroundings, and a lid with two holes, allowing insertion of a thermometer and a stirring rod. The inner cup holds a known amount of a solvent, usually water, that absorbs the heat from the reaction. When the reaction occurs, the outer cup provides insulation. Then

 * $$C_\text{p} = \frac {W\Delta H}{M\Delta T}$$

where

 * $$C_\text{p}$$, Specific heat at constant pressure
 * $$\Delta H$$, Enthalpy of solution
 * $$\Delta T$$, Change in temperature
 * $$W$$, mass of solvent
 * $$M$$, molecular mass of solvent

The measurement of heat using a simple calorimeter, like the coffee cup calorimeter, is an example of constant-pressure calorimetry, since the pressure (atmospheric pressure) remains constant during the process. Constant-pressure calorimetry is used in determining the changes in enthalpy occurring in solution. Under these conditions the change in enthalpy equals the heat.

Commercial calorimeters operate in a similar way. The semi-adiabatic (isoperibol) calorimeters measure temperature changes up to 10$−6$°C and account for heat loss through the walls of the reaction vessel to the environment, hence, semi-adiabatic. The reaction vessel is a dewar flask which is immersed in a constant temperature bath. This provides a constant heat leak rate that can be corrected through the software. The heat capacity of the reactants (and the vessel) are measured by introducing a known amount of heat using a heater element (voltage and current) and measuring the temperature change.

Adiabatic calorimeters most commonly used in materials science research to study reactions that occur at a constant pressure and volume. They are particularly useful for determining the heat capacity of substances, measuring the enthalpy changes of chemical reactions, and studying the thermodynamic properties of materials.

Differential scanning calorimeter
In a differential scanning calorimeter (DSC), heat flow into a sample—usually contained in a small aluminium capsule or 'pan'—is measured differentially, i.e., by comparing it to the flow into an empty reference pan.

In a heat flux DSC, both pans sit on a small slab of material with a known (calibrated) heat resistance K. The temperature of the calorimeter is raised linearly with time (scanned), i.e., the heating rate
 * dT/dt = β

is kept constant. This time linearity requires good design and good (computerized) temperature control. Of course, controlled cooling and isothermal experiments are also possible.

Heat flows into the two pans by conduction. The flow of heat into the sample is larger because of its heat capacity Cp. The difference in flow dq/dt induces a small temperature difference ΔT across the slab. This temperature difference is measured using a thermocouple. The heat capacity can in principle be determined from this signal:

 * $$\Delta T = K {dq \over dt} = K C_\text{p}\, \beta$$

Note that this formula (equivalent to Newton's law of heat flow) is analogous to, and much older than, Ohm's law of electric flow:

When suddenly heat is absorbed by the sample (e.g., when the sample melts), the signal will respond and exhibit a peak.

 * $${dq \over dt} = C_\text{p} \beta + f(t, T) $$

From the integral of this peak the enthalpy of melting can be determined, and from its onset the melting temperature.

Differential scanning calorimetry is a workhorse technique in many fields, particularly in polymer characterization.

A modulated temperature differential scanning calorimeter (MTDSC) is a type of DSC in which a small oscillation is imposed upon the otherwise linear heating rate.

This has a number of advantages. It facilitates the direct measurement of the heat capacity in one measurement, even in (quasi-)isothermal conditions. It permits the simultaneous measurement of heat effects that respond to a changing heating rate (reversing) and that don't respond to the changing heating rate (non-reversing). It allows for the optimization of both sensitivity and resolution in a single test by allowing for a slow average heating rate (optimizing resolution) and a fast changing heating rate (optimizing sensitivity).

Safety screening:- DSC may also be used as an initial safety screening tool. In this mode the sample will be housed in a non-reactive crucible (often gold, or gold-plated steel), and which will be able to withstand pressure (typically up to 100 bar). The presence of an exothermic event can then be used to assess the stability of a substance to heat. However, due to a combination of relatively poor sensitivity, slower than normal scan rates (typically 2–3°/min - due to much heavier crucible) and unknown activation energy, it is necessary to deduct about 75–100 °C from the initial start of the observed exotherm to suggest a maximum temperature for the material. A much more accurate data set can be obtained from an adiabatic calorimeter, but such a test may take 2–3 days from ambient at a rate of 3 °C increment per half hour.

Isothermal titration calorimeter
In an isothermal titration calorimeter, the heat of reaction is used to follow a titration experiment. This permits determination of the midpoint (stoichiometry) (N) of a reaction as well as its enthalpy (delta H), entropy (delta S) and of primary concern the binding affinity (Ka)

The technique is gaining in importance particularly in the field of biochemistry, because it facilitates determination of substrate binding to enzymes. The technique is commonly used in the pharmaceutical industry to characterize potential drug candidates.

Continuous Reaction Calorimeter
The Continuous Reaction Calorimeter is especially suitable to obtain thermodynamic information for a scale-up of continuous processes in tubular reactors. This is useful because the released heat can strongly depend on the reaction control, especially for non-selective reactions. With the Continuous Reaction Calorimeter an axial temperature profile along the tube reactor can be recorded and the specific heat of reaction can be determined by means of heat balances and segmental dynamic parameters. The system must consist of a tubular reactor, dosing systems, preheaters, temperature sensors and flow meters.

In traditional heat flow calorimeters, one reactant is added continuously in small amounts, similar to a semi-batch process, in order to obtain a complete conversion of the reaction. In contrast to the tubular reactor, this leads to longer residence times, different substance concentrations and flatter temperature profiles. Thus, the selectivity of not well-defined reactions can be affected. This can lead to the formation of by-products or consecutive products which alter the measured heat of reaction, since other bonds are formed. The amount of by-product or secondary product can be found by calculating the yield of the desired product.

If the heat of reaction measured in the HFC (Heat flow calorimetry) and PFR calorimeter differ, most probably some side reactions have occurred. They could for example be caused by different temperatures and residence times. The totally measured Qr is composed of partially overlapped reaction enthalpies (ΔHr) of main and side reactions, depending on their degrees of conversion (U).

Calorimetry in Geothermal Reactors
Calorimeters can be used to measure the efficiency of geothermal energy conversion processes. Through measuring the heat input and output of the process, engineers can determine how effective the plant is at converting geothermal energy into usable electricity or other forms of energy.

Calorimeters can also monitor the quality of the steam extracted from the geothermal resource. By analyzing the heat content of the steam, engineers can ensure that the resource meets the required specifications for efficient energy production.

title: Calorimeter


text:
Partial pressure

In a mixture of gases, each constituent gas has a partial pressure which is the notional pressure of that constituent gas as if it alone occupied the entire volume of the original mixture at the same temperature. The total pressure of an ideal gas mixture is the sum of the partial pressures of the gases in the mixture (Dalton's Law).

The partial pressure of a gas is a measure of thermodynamic activity of the gas's molecules. Gases dissolve, diffuse, and react according to their partial pressures but not according to their concentrations in gas mixtures or liquids. This general property of gases is also true in chemical reactions of gases in biology. For example, the necessary amount of oxygen for human respiration, and the amount that is toxic, is set by the partial pressure of oxygen alone. This is true across a very wide range of different concentrations of oxygen present in various inhaled breathing gases or dissolved in blood; consequently, mixture ratios, like that of breathable 20% oxygen and 80% Nitrogen, are determined by volume instead of by weight or mass. Furthermore, the partial pressures of oxygen and carbon dioxide are important parameters in tests of arterial blood gases. That said, these pressures can also be measured in, for example, cerebrospinal fluid.

Symbol
The symbol for pressure is usually $p$ or $pp$ which may use a subscript to identify the pressure, and gas species are also referred to by subscript. When combined, these subscripts are applied recursively.

Examples:
 * $$P_1$$ or $$p_1$$ = pressure at time 1
 * P_\ce{H2} or p_\ce{H2} = partial pressure of hydrogen
 * or or PaO2 = arterial partial pressure of oxygen
 * or or PvO2 = venous partial pressure of oxygen

Dalton's law of partial pressures
Dalton's law expresses the fact that the total pressure of a mixture of ideal gases is equal to the sum of the partial pressures of the individual gases in the mixture. This equality arises from the fact that in an ideal gas, the molecules are so far apart that they do not interact with each other. Most actual real-world gases come very close to this ideal. For example, given an ideal gas mixture of nitrogen (N2), hydrogen (H2) and ammonia (NH3):

where:
 * $$p $$ = total pressure of the gas mixture
 * p_\ce{N2} = partial pressure of nitrogen (N2)
 * p_\ce{H2} = partial pressure of hydrogen (H2)
 * p_\ce{NH3} = partial pressure of ammonia (NH3)

Ideal gas mixtures
Ideally the ratio of partial pressures equals the ratio of the number of molecules. That is, the mole fraction $$x_{\mathrm{i}}$$ of an individual gas component in an ideal gas mixture can be expressed in terms of the component's partial pressure or the moles of the component: $$x_{\mathrm{i}} = \frac{p_{\mathrm{i}}}{p} = \frac{n_{\mathrm{i}}}{n}$$

and the partial pressure of an individual gas component in an ideal gas can be obtained using this expression: $$p_{\mathrm{i}} = x_{\mathrm{i}} \cdot p$$

The mole fraction of a gas component in a gas mixture is equal to the volumetric fraction of that component in a gas mixture.

The ratio of partial pressures relies on the following isotherm relation: $$\frac{V_{\rm X}}{V_{\rm tot}} = \frac{p_{\rm X}}{p_{\rm tot}} = \frac{n_{\rm X}}{n_{\rm tot}}$$
 * VX is the partial volume of any individual gas component (X)
 * Vtot is the total volume of the gas mixture
 * pX is the partial pressure of gas X
 * ptot is the total pressure of the gas mixture
 * nX is the amount of substance of gas (X)
 * ntot is the total amount of substance in gas mixture

Partial volume (Amagat's law of additive volume)
The partial volume of a particular gas in a mixture is the volume of one component of the gas mixture. It is useful in gas mixtures, e.g. air, to focus on one particular gas component, e.g. oxygen.

It can be approximated both from partial pressure and molar fraction: $$V_{\rm X} = V_{\rm tot} \times \frac{p_{\rm X}}{p_{\rm tot}} = V_{\rm tot} \times \frac{n_{\rm X}}{n_{\rm tot}}$$
 * VX is the partial volume of an individual gas component X in the mixture
 * Vtot is the total volume of the gas mixture
 * pX is the partial pressure of gas X
 * ptot is the total pressure of the gas mixture
 * nX is the amount of substance of gas X
 * ntot is the total amount of substance in the gas mixture

Vapor pressure

Vapor pressure is the pressure of a vapor in equilibrium with its non-vapor phases (i.e., liquid or solid). Most often the term is used to describe a liquid's tendency to evaporate. It is a measure of the tendency of molecules and atoms to escape from a liquid or a solid. A liquid's atmospheric pressure boiling point corresponds to the temperature at which its vapor pressure is equal to the surrounding atmospheric pressure and it is often called the normal boiling point.

The higher the vapor pressure of a liquid at a given temperature, the lower the normal boiling point of the liquid.

The vapor pressure chart displayed has graphs of the vapor pressures versus temperatures for a variety of liquids. As can be seen in the chart, the liquids with the highest vapor pressures have the lowest normal boiling points.

For example, at any given temperature, methyl chloride has the highest vapor pressure of any of the liquids in the chart. It also has the lowest normal boiling point (−24.2 °C), which is where the vapor pressure curve of methyl chloride (the blue line) intersects the horizontal pressure line of one atmosphere (atm) of absolute vapor pressure. At higher altitudes, the atmospheric pressure is less than that at sea level, so boiling points of liquids are reduced. At the top of Mount Everest, the atmospheric pressure is approximately 0.333 atm, so by using the graph, the boiling point of diethyl ether would be approximately 7.5 °C versus 34.6 °C at sea level (1 atm).

Equilibrium constants of reactions involving gas mixtures
It is possible to work out the equilibrium constant for a chemical reaction involving a mixture of gases given the partial pressure of each gas and the overall reaction formula. For a reversible reaction involving gas reactants and gas products, such as:

the equilibrium constant of the reaction would be: $$K_\mathrm{p} = \frac{p_C^c\, p_D^d} {p_A^a\, p_B^b}$$

For reversible reactions, changes in the total pressure, temperature or reactant concentrations will shift the equilibrium so as to favor either the right or left side of the reaction in accordance with Le Chatelier's Principle. However, the reaction kinetics may either oppose or enhance the equilibrium shift. In some cases, the reaction kinetics may be the overriding factor to consider.

Henry's law and the solubility of gases
Gases will dissolve in liquids to an extent that is determined by the equilibrium between the undissolved gas and the gas that has dissolved in the liquid (called the solvent). The equilibrium constant for that equilibrium is:

where:
 * $$k$$ = the equilibrium constant for the solvation process
 * $$p_x$$ = partial pressure of gas $$x$$ in equilibrium with a solution containing some of the gas
 * $$C_x$$ = the concentration of gas $$x$$ in the liquid solution

The form of the equilibrium constant shows that the concentration of a solute gas in a solution is directly proportional to the partial pressure of that gas above the solution. This statement is known as Henry's law and the equilibrium constant $$k$$ is quite often referred to as the Henry's law constant.

Henry's law is sometimes written as:

where $$k'$$ is also referred to as the Henry's law constant. As can be seen by comparing equations ($$) and ($$) above, $$k'$$ is the reciprocal of $$k$$. Since both may be referred to as the Henry's law constant, readers of the technical literature must be quite careful to note which version of the Henry's law equation is being used.

Henry's law is an approximation that only applies for dilute, ideal solutions and for solutions where the liquid solvent does not react chemically with the gas being dissolved.

In diving breathing gases
In underwater diving the physiological effects of individual component gases of breathing gases are a function of partial pressure.

Using diving terms, partial pressure is calculated as:
 * partial pressure = (total absolute pressure) × (volume fraction of gas component)

For the component gas "i":
 * pi = P × Fi

For example, at 50 m underwater, the total absolute pressure is 6 bar (i.e., 1 bar of atmospheric pressure + 5 bar of water pressure) and the partial pressures of the main components of air, oxygen 21% by volume and nitrogen approximately 79% by volume are:
 * pN2 = 6 bar × 0.79 = 4.7 bar absolute
 * pO2 = 6 bar × 0.21 = 1.3 bar absolute

The minimum safe lower limit for the partial pressures of oxygen in a breathing gas mixture for diving is 0.16 bar absolute. Hypoxia and sudden unconsciousness can become a problem with an oxygen partial pressure of less than 0.16 bar absolute. Oxygen toxicity, involving convulsions, becomes a problem when oxygen partial pressure is too high. The NOAA Diving Manual recommends a maximum single exposure of 45 minutes at 1.6 bar absolute, of 120 minutes at 1.5 bar absolute, of 150 minutes at 1.4 bar absolute, of 180 minutes at 1.3 bar absolute and of 210 minutes at 1.2 bar absolute. Oxygen toxicity becomes a risk when these oxygen partial pressures and exposures are exceeded. The partial pressure of oxygen also determines the maximum operating depth of a gas mixture.

Narcosis is a problem when breathing gases at high pressure. Typically, the maximum total partial pressure of narcotic gases used when planning for technical diving may be around 4.5 bar absolute, based on an equivalent narcotic depth of 35 m.

The effect of a toxic contaminant such as carbon monoxide in breathing gas is also related to the partial pressure when breathed. A mixture which may be relatively safe at the surface could be dangerously toxic at the maximum depth of a dive, or a tolerable level of carbon dioxide in the breathing loop of a diving rebreather may become intolerable within seconds during descent when the partial pressure rapidly increases, and could lead to panic or incapacitation of the diver.

In medicine
The partial pressures of particularly oxygen ($$p_\mathrm{O_2}$$) and carbon dioxide ($$p_\mathrm{CO_2}$$) are important parameters in tests of arterial blood gases, but can also be measured in, for example, cerebrospinal fluid.

title: Partial pressure


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SS General von Steuben

SS General von Steuben was a German passenger liner and later an armed transport ship of the German Navy that was sunk in the Baltic Sea during World War II. She was launched in 1923 as München (after the German city, sometimes spelled Muenchen), renamed General von Steuben in 1930 (after the famous German officer of the American Revolutionary War), and renamed Steuben in 1938.

During World War II, the ship served as a troop accommodation vessel, and from 1944 as an armed transport. On 10 February 1945, while evacuating German military personnel, wounded soldiers, and civilian refugees during Operation Hannibal, the ship was torpedoed by the Soviet submarine S-13 and sank. An estimated 4,000 people lost their lives in the sinking.

Early history
In 1923, München became the first German trans-Atlantic passenger liner to be launched, and also the first to enter New York Harbor, since the end of World War I. She arrived in July 1923 on her maiden transatlantic voyage.

1930 fire and sinking
On 11 February 1930, after München docked in New York City and discharged passengers and most of her crew from a voyage from Bremen, Germany, a fire broke out in a paint locker on board and quickly spread to another storage hold. The massive fire and explosion resulted in a five-alarm fire and all of the city's fire equipment was sent to the burning ship. The fire could not be controlled and the ship sank next to the wharf where it had docked.

In one of the largest shipping salvage efforts of its time, München was raised, towed to a dry dock, repaired, and returned to service. Shortly afterwards, the ship's owner renamed her General von Steuben.

World War II
The ship, now called Steuben, was commissioned in 1939 as a Kriegsmarine accommodation ship. In 1944, she was pressed into service as an armed transport ship, taking German troops to eastern Baltic ports and returning wounded troops to Kiel.

Operation Hannibal
Along with the MV Wilhelm Gustloff and numerous other vessels, Steuben was part of the largest evacuation by sea in modern times. The Operation Hannibal evacuations surpassed the British evacuation at Dunkirk in both size of the operation and number of people evacuated.

By early January 1945, Grossadmiral Karl Dönitz realized that Germany was soon to be defeated. Wishing to save his submariners, he radioed a coded message on 23 January 1945 to the Baltic Sea port of Gotenhafen (the Polish city and port of Gdynia under German occupation) to evacuate to the West, under the code name Operation Hannibal.

Submariners at that point were schooled and housed in ships floating in the Baltic ports, most of them at Gotenhafen. Among the ships were SS Deutschland (1923), SS Hamburg (1925), Hansa, and Wilhelm Gustloff.

Notwithstanding the losses suffered during the operation, over two million people were evacuated ahead of the Red Army's advance into East Prussia and Danzig (now Gdańsk, Poland).

In the winter of 1945, East Prussian refugees headed west, away from the city of Königsberg and ahead of the Soviet advance into the Baltic States and East Prussia. Thousands fled to the Baltic seaport at Pillau (now Baltiysk, Russia), hoping to board ships that would carry them to the relative safety of Western Germany. Steuben was part of the fleet sent for the purpose.

Final voyage
On 9 February 1945, the 14,660-ton Steuben sailed from Pillau, near Königsberg on the Baltic coast, for Swinemünde (now Świnoujście, Poland). Official reports listed 2,800 wounded German soldiers; 800 civilians; 100 returning soldiers; 270 navy medical personnel (including doctors, nurses and auxiliaries); 12 nurses from Pillau; 64 crew for the ship's anti-aircraft guns, 61 naval personnel, radio operators, signal men, machine operators and administrators, plus 160 merchant navy crewmen, for a total of 4,267 people on board. Due to the rapid evacuation ahead of the Red Army's advance, many Eastern German and Baltic refugees boarded the Steuben without being registered, increasing the number of those on board to approximately 5,200.

Just before midnight on 9 February, the Soviet submarine S-13, commanded by Alexander Marinesko, fired two torpedoes 14 seconds apart at the Steuben; both hit her starboard bow, just below the bridge, where many of the crew were sleeping. Most were killed by the impact of the torpedoes. According to survivors, the Steuben sank by the bow and listed severely to starboard before taking her final plunge, within about 20 minutes of the torpedo impacts. An estimated 4,500 people died in the sinking. German torpedo boat T-196 hastily pulled up beside Steuben as she sank; its crew pulled about 300 survivors straight from Steuben's slanting decks and brought them to Kolberg in Pomerania (today Kołobrzeg, Poland). A total of 650 people were rescued from the Steuben.

Wreck
The Steuben wreck was found and identified in May 2004 by Polish Navy hydrographical vessel ORP Arctowski. Pictures and graphics appeared in a 2005 National Geographic article.

The wreck lies on its port side at about 70 m in depth, and the hull reaches up to 50 m in depth. The ship was mostly intact when it was found.

In July 2021, German news magazine Der Spiegel reported that the wreck had been plundered and severely damaged in the process. The wreck is an official war grave, and entering it is illegal. Due to international treaties, the wreck remains property of the German state, but Poland is responsible for its protection. Over the past decade, looting has become one of the biggest reasons for the deteriorating condition of shipwrecks in the Baltic sea.

title: SS General von Steuben