Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalised seizures. It has been used both alone and as add-on therapy in people with bipolar disorder who have had no success with other treatments. It is taken by mouth.
Common side effects include nausea, vomiting, dizziness, drowsiness, double vision and trouble with walking. Serious side effects may include anaphylaxis, liver problems, pancreatitis, suicide ideation, and an abnormal heart beat. While use during pregnancy may harm the baby, use may be less risky than having a seizure. Use is not recommended during breastfeeding. In those with an allergy to carbamazepine there is a 25% risk of problems with oxcarbazepine. How it works is not entirely clear.
Oxcarbazepine was patented in 1969 and came into medical use in 1990. It is available as a generic medication. In 2022, it was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Brief History
First made in 1966, it was patent-protected by Geigy in 1969 through DE 2011087. It was approved for use as an anticonvulsant in Denmark in 1990, Spain in 1993, Portugal in 1997, and eventually for all other EU countries in 1999. It was approved in the US in 2000. In September 2010, Novartis, of which Geigy are part of its corporate roots, pleaded guilty to marketing Trileptal for the unapproved uses of neuropathic pain and bipolar disorder.
Medical Uses
Neurology
Oxcarbazepine is an anticonvulsant used to reduce the occurrence of epileptic episodes, and is not intended to cure epilepsy. Oxcarbazepine is used alone or in combination with other medications for the treatment of focal (partial) seizures in adults. In paediatric populations, it can be used by itself for the treatment of partial seizures for children 4 years and older, or in combination with other medications for children 2 years and older. There is some evidence to support its effectiveness in reducing seizure frequency when used as an add-on therapy for drug-resistant focal epilepsy but there are concerns over tolerability.
Psychiatry
Oxcarbazepine (brand name Trileptal), has been historically used off-label by psychiatrists as a mood stabiliser. However, due to the limited data supporting efficacy it is typically reserved for patients for whom other medications have not worked or are contraindicated.
Side Effects
Side effects are dose-dependent. The most common include dizziness, blurred or double vision, nystagmus, ataxia, fatigue, headaches, nausea, vomiting, sleepiness, difficulty in concentration, and mental sluggishness. The incidence of movement disorders appears to be lower compared to carbamazepine.
Other, rare, side effects of oxcarbazepine include severe low blood sodium (hyponatremia), anaphylaxis / angioedema, hypersensitivity (especially if experienced with carbamazepine), toxic epidermal necrolysis, Stevens–Johnson syndrome, and thoughts of suicide.
Measurement of serum sodium levels should be considered in maintenance treatment or if symptoms of hyponatremia develop. Low blood sodium is seen in 20–30% of people taking oxcarbazepine, and 8–12% of those experience severe hyponatremia. Some side effects, such as headaches, are more pronounced shortly after a dose is taken and tend to fade with time (60 to 90 minutes). Other side effects include stomach pain, tremor, rash, diarrhoea, constipation, decreased appetite, and dry mouth. Photosensitivity is a potential side-effect and people could experience severe sunburns as a result of sun exposure.
Oxcarbazepine may lead to hypothyroxinemia. The well-known reduction in free and total thyroxine concentration may be due to both peripheral and central mechanisms.
Pregnancy
Oxcarbazepine is pregnancy category C in the US. There is limited data supporting its safety in pregnancy. Several alternative medications with similar efficacy profiles provide significantly more robust data to support safety during pregnancy. However limited recent research shows similar rates of foetal malformations in exposed pregnancies to the general non-teratogen exposed population. Careful consideration of the risks, benefits, alternatives, and expert advise is needed when considering Oxcarbazepine use during pregnancy.
Historically Oxcarbazepine was considered to be teratogenic in humans due to animal studies which have shown increased foetal abnormalities in pregnant rats and rabbits exposed to oxcarbazepine during pregnancy. Additionally it’s similar structure of to carbamazepine, raised concern as it is teratogenic in humans (pregnancy category D).
Breastfeeding
Oxcarbazepine and its metabolite licarbazepine are both present in human breast milk and thus, some of the active drug can be transferred to a nursing infant. When considering whether to continue this medication in nursing mothers, the impact of the drug’s side effect profile on the infant should be weighed against its anti-epileptic benefit for the mother.
Interactions
Oxcarbazepine, licarbazepine and many other common drugs influence each other through interaction with the cytochrome P450 family of enzymes. This leads to a cluster of dozens of common drugs interacting with one another to varying degrees, some of which are especially noteworthy.
Oxcarbazepine and licarbazepine are potent inhibitors of CYP2C19 and thus have the potential to increase plasma concentration of drugs, which are metabolised through this pathway. Other antiepileptics, which are CYP2C19 substrates and thus may be metabolised at a reduced rate when combined with oxcarbazepine, include diazepam, hexobarbital, mephenytoin, methylphenobarbital, nordazepam, phenobarbital, phenytoin, and primidone.
In addition, oxcarbazepine and licarbazepine are CYP3A4 and CYP3A5 inducers and thus have the potential to decrease the plasma concentration of CYP3A4 and CYP3A5 substrates, including calcium channel antagonists against high blood pressure and oral contraceptives. However, whether the extent of CYP3A4/5 induction at therapeutic doses reaches clinical significance is unclear.
Pharmacology
Oxcarbazepine is a prodrug, which is largely metabolised to its pharmacologically active 10-monohydroxy derivative licarbazepine (sometimes abbreviated MHD). Oxcarbazepine and MHD exert their action by blocking voltage-sensitive sodium channels, thus leading to the stabilisation of hyper-excited neural membranes, suppression of repetitive neuronal firing and diminishment propagation of synaptic impulses. Furthermore, anticonvulsant effects of these compounds could be attributed to enhanced potassium conductance and modulation of high-voltage activated calcium channels.
Pharmacokinetics
Oxcarbazepine has high bioavailability upon oral administration. In a study in humans, only 2% of oxcarbazepine remained unchanged, 70% were reduced to licarbazepine; the rest were minor metabolites. The half-life of oxcarbazepine is considered to be about 2 hours, whereas licarbazepine has a half-life of nine hours. Through its chemical difference to carbamazepine metabolic epoxidation is avoided, reducing hepatic risks. Licarbazepine is metabolised by conjugation with Glucuronic acid. Approximately 4% are oxidised to the inactive 10,11-dihydroxy derivative. Elimination is almost completely renal, with faeces accounting to less than 4%. 80% of the excreted substances are to be attributed to licarbazepine or its glucuronides.
Pharmacodynamics
Both oxcarbazepine and licarbazepine were found to show anticonvulsant properties in seizure models done on animals. These compounds had protective functions whenever tonic extension seizures were induced electrically, but such protection was less apparent whenever seizures were induced chemically. There was no observable tolerance during a four weeks course of treatment with daily administration of oxcarbazepine or licarbazepine in electroshock test on mice and rats. Most of the antiepileptic activity can be attributed to licarbazepine. Aside from its reduction in side effects, it is presumed to have the same main mechanism as carbamazepine, sodium channel inhibition, and is generally used to treat the same conditions.
Pharmacogenetics
The human leukocyte antigen (HLA) allele B*1502 has been associated with an increased incidence of Stevens–Johnson syndrome and toxic epidermal necrolysis in people treated with carbamazepine, and thus those treated with oxcarbazepine might have similar risks. People of Asian descent are more likely to carry this genetic variant, especially some Malaysian populations, Koreans (2%), Han Chinese (2–12%), Indians (6%), Thai (8%), and Philippines (15%). Therefore, it has been suggested to consider genetic testing in these people prior to initiation of treatment.
Structure
Oxcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon–carbon double bond on the dibenzazepine ring at the 10 position (10-keto). This difference helps reduce the impact on the liver of metabolising the drug, and also prevents the serious forms of anaemia or agranulocytosis occasionally associated with carbamazepine. Aside from this reduction in side effects, it is thought to have the same mechanism as carbamazepine — sodium channel inhibition (presumed to be the main mechanism of action) – and is generally used to treat the same conditions.
Oxcarbazepine is a prodrug which is activated to licarbazepine in the liver.
Research
Antiepileptics are a key pharmacological therapy used in the treatment of bipolar disorder. Research has investigated the use of oxcarbazepine as a mood stabiliser in bipolar disorder, with further evidence needed to fully assess its suitability. Oxcarbazepine used in conjunction with lithium has been shown to be effective in the maintenance phase.
It may be beneficial in trigeminal neuralgia.
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Certain lithium compounds, also known as lithium salts, are used as psychiatric medication, primarily for bipolar disorder and for major depressive disorder. Lithium is taken orally (by mouth).
Common side effects include increased urination, shakiness of the hands, and increased thirst. Serious side effects include hypothyroidism, diabetes insipidus, and lithium toxicity. Blood level monitoring is recommended to decrease the risk of potential toxicity. If levels become too high, diarrhoea, vomiting, poor coordination, sleepiness, and ringing in the ears may occur. Lithium is teratogenic and can cause birth defects at high doses, especially during the first trimester of pregnancy. The use of lithium while breastfeeding is controversial; however, many international health authorities advise against it, and the long-term outcomes of perinatal lithium exposure have not been studied. The American Academy of Paediatrics lists lithium as contraindicated for pregnancy and lactation. The United States Food and Drug Administration (FDA categorises lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation.
Lithium salts are classified as mood stabilisers. Lithium’s mechanism of action is not known.
In the nineteenth century, lithium was used in people who had gout, epilepsy, and cancer. Its use in the treatment of mental disorders began with Carl Lange in Denmark and William Alexander Hammond in New York City, who used lithium to treat mania from the 1870s onwards, based on now-discredited theories involving its effect on uric acid. Use of lithium for mental disorders was re-established (on a different theoretical basis) in 1948 by John Cade in Australia. Lithium carbonate is on the World Health Organisation’s List of Essential Medicines, and is available as a generic medication. In 2022, it was the 212th most commonly prescribed medication in the United States, with more than 1 million prescriptions. It appears to be underused in older people, and in certain countries, for reasons including patients’ negative beliefs about lithium.
Brief History
Lithium was first used in the 19th century as a treatment for gout after scientists discovered that, at least in the laboratory, lithium could dissolve uric acid crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic. Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark and William Alexander Hammond in New York City used lithium to treat mania from the 1870s onwards.
By the turn of the 20th century, as theory regarding mood disorders evolved and so-called “brain gout” disappeared as a medical entity, the use of lithium in psychiatry was largely abandoned; however, several lithium preparations were still produced for the control of renal calculi and uric acid diathesis. As accumulating knowledge indicated a role for excess sodium intake in hypertension and heart disease, lithium salts were prescribed to patients for use as a replacement for dietary table salt (sodium chloride). This practice and the sale of lithium itself were both banned in the United States in February 1949, following the publication of reports detailing side effects and deaths.
Also in 1949, the Australian psychiatrist John Cade and Australian biochemist Shirley Andrews rediscovered the usefulness of lithium salts in treating mania while working at the Royal Park Psychiatric Hospital in Victoria. They were injecting rodents with urine extracts taken from manic patients in an attempt to isolate a metabolic compound which might be causing mental symptoms. Since uric acid in gout was known to be psychoactive, (adenosine receptors on neurons are stimulated by it; caffeine blocks them), they needed soluble urate for a control. They used lithium urate, already known to be the most soluble urate compound, and observed that it caused the rodents to become tranquil. Cade and Andrews traced the effect to the lithium-ion itself, and after Cade ingested lithium himself to ensure its safety in humans, he proposed lithium salts as tranquilisers. He soon succeeded in controlling mania in chronically hospitalised patients with them. This was one of the first successful applications of a drug to treat mental illness, and it opened the door for the development of medicines for other mental problems in the next decades.
The rest of the world was slow to adopt this treatment, largely because of deaths that resulted from even relatively minor overdosing, including those reported from the use of lithium chloride as a substitute for table salt. Largely through the research and other efforts of Denmark’s Mogens Schou and Paul Baastrup in Europe, and Samuel Gershon and Baron Shopsin in the US, this resistance was slowly overcome. Following the recommendation of the APA Lithium Task Force (William Bunney, Irvin Cohen (Chair), Jonathan Cole, Ronald R. Fieve, Samuel Gershon, Robert Prien, and Joseph Tupin[133]), the application of lithium in manic illness was approved by the FDA in 1970, becoming the 50th nation to do so.
Lithium has now become a part of Western popular culture. Characters in Pi, Premonition, Stardust Memories, American Psycho, Garden State, and An Unmarried Woman all take lithium. It’s the chief constituent of the calming drug in Ira Levin’s dystopian This Perfect Day. Sirius XM Satellite Radio in North America has a 1990s alternative rock station called Lithium, and several songs refer to the use of lithium as a mood stabiliser. These include: “Equilibrium met Lithium” by South African artist Koos Kombuis, “Lithium” by Evanescence, “Lithium” by Nirvana, “Lithium and a Lover” by Sirenia, “Lithium Sunset”, from the album Mercury Falling by Sting, and “Lithium” by Thin White Rope.
7 Up
As with cocaine in Coca-Cola, lithium was widely marketed as one of several patent medicine products popular in the late 19th and early 20th centuries and was the medicinal ingredient of a refreshment beverage. Charles Leiper Grigg, who launched his St. Louis-based company The Howdy Corporation, invented a formula for a lemon-lime soft drink in 1920. The product, originally named “Bib-Label Lithiated Lemon-Lime Soda”, was launched two weeks before the Wall Street Crash of 1929. It contained the mood stabiliser lithium citrate, and was one of many patent medicine products popular in the late-19th and early-20th centuries. Its name was soon changed to 7 Up. All American beverage makers were forced to remove lithium from beverages in 1948. Despite the ban, in 1950, the Painesville Telegraph still carried an advertisement for a lithiated lemon beverage.
Medical Uses
In 1970, lithium was approved by the FDA for the treatment of bipolar disorder, which remains its primary use in the US. It is sometimes used when other treatments are not effective in a number of other conditions, including major depression, schizophrenia, disorders of impulse control, and some psychiatric disorders in children. Because the FDA has not approved lithium for the treatment of other disorders, such use is off-label.
Bipolar Disorder
Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilise mood and prevent manic episodes, but it may also be helpful in the acute treatment of manic episodes. Although recommended by treatment guidelines for the treatment of depression in bipolar disorder, the evidence that lithium is superior to placebo for acute depression is low-quality; atypical antipsychotics are considered more effective for treating acute depressive episodes. Lithium carbonate treatment was previously considered to be unsuitable for children; however, more recent studies show its effectiveness for treatment of early-onset bipolar disorder in children as young as eight. The required dosage is slightly less than the toxic level (representing a low therapeutic index), requiring close monitoring of blood levels of lithium carbonate during treatment. Within the therapeutic range there is a dose-response relationship. A limited amount of evidence suggests lithium carbonate may contribute to the treatment of substance use disorders for some people with bipolar disorder. Although it is believed that lithium prevents suicide in people with bipolar disorder, a 2022 systematic review found that:
“Evidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour.”
Schizophrenic Disorders
Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; it has limited effectiveness when used alone. The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied.
Major Depressive Disorder
Lithium is widely prescribed as an adjunct treatment for depression.
Augmentation
If therapy with antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]) does not fully treat and discontinue the symptoms of major depressive disorder (MDD) (also known as refractory depression or treatment resistant depression [TRD]) then a second augmentation agent is sometimes added to the therapy. Lithium is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomised controlled trials and it has been prescribed (off-label) for this purpose since the 1980s. A 2019 systematic review found some evidence of the clinical utility of adjunctive lithium, but the majority of supportive evidence is dated.
While SSRIs have been mentioned above as a drug class in which lithium is used to augment, there are other classes in which lithium is added to increase effectiveness. Such classes are antipsychotics (used for bipolar disorder) as well as antiepileptic drugs (used for both psychiatric and epileptic cases). Lamotrigine and topiramate are two specific antiepileptic drugs in which lithium is used to augment.
Monotherapy
There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as tricyclic antidepressants. A recent study concluded that lithium works best on chronic and recurrent depression when compared to modern antidepressant (i.e. citalopram) but not for patients with no history of depression. A 2019 systemic review found no evidence to support the use of lithium for monotherapy.
Prevention of Suicide
Lithium is widely believed to prevent suicide and is often used in clinical practice towards that end. However, meta-analyses, faced with evidence base limitations, have yielded differing results, and it therefore remains unclear whether or not lithium is efficacious in the prevention of suicide. However, some evidence suggests it is effective in significantly reducing the risk of self-harm and unintentional injury for bipolar disorder in comparison to no treatment and to antipsychotics or valporate. According to meta-analyses, the increased presence of lithium in drinking water is correlated with lower overall suicide rates, especially among men. It is noted that further testing is needed to confirm this benefit.
Alzheimer’s Disease
Alzheimer’s disease affects forty-five million people and is the fifth leading cause of death in the 65-plus population. There is no complete cure for the disease, currently. However, lithium is being evaluated for its effectiveness as a potential therapeutic measure. One of the leading causes of Alzheimer’s is the hyperphosphorylation of the tau protein by the enzyme GSK-3, which leads to the overproduction of amyloid peptides that cause cell death. To combat this toxic amyloid aggregation, lithium upregulates the production of neuroprotectors and neurotrophic factors, as well as inhibiting the GSK-3 enzyme. Lithium also stimulates neurogenesis within the hippocampus, making it thicker. Yet another cause of Alzheimer’s disease is the dysregulation of calcium ions within the brain. Too much or too little calcium within the brain can lead to cell death. Lithium can restore intracellular calcium homeostasis by inhibiting the wrongful influx of calcium upstream. It also promotes the redirection of the influx of calcium ions into the lumen of the endoplasmic reticulum of the cells to reduce the oxidative stress within the mitochondria.
In 2009, a study was performed by Hampel and colleagues that asked patients with Alzheimer’s to take a low dose of lithium daily for three months; it resulted in a significant slowing of cognitive decline, benefitting patients being in the prodromal stage the most. Upon a secondary analysis, the brains of the Alzheimer’s patients were studied and shown to have an increase in BDNF markers, meaning they had actually shown cognitive improvement. Another study, a population study this time by Kessing et al., showed a negative correlation between Alzheimer’s disease deaths and the presence of lithium in drinking water. Areas with increased lithium in their drinking water showed less dementia overall in their population.
Monitoring
Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of sodium and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst.
Lithium concentrations in whole blood, plasma, serum, or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the range of 0.5–1.3 mmol/L (0.5–1.3 mEq/L) in well-controlled people, but may increase to 1.8–2.5 mmol/L in those who accumulate the drug over time and to 3–10 mmol/L in acute overdose.
Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4[a][b] to 1.2 mmol/L on samples taken 12 hours after the preceding dose.
Given the rates of thyroid dysfunction, thyroid parameters should be checked before lithium is instituted and monitored after 3–6 months and then every 6–12 months.
Given the risks of kidney malfunction, serum creatinine, and eGFR should be checked before lithium is instituted and monitored after 3–6 months at regular intervals. Patients who have a rise in creatinine on three or more occasions, even if their eGFR is > 60 ml/min/ 1.73m2 require further evaluation, including a urinalysis for haematuria, and proteinuria, a review of their medical history with attention paid to cardiovascular, urological, and medication history, and blood pressure control and management. Overt proteinuria should be further quantified with a urine protein-to-creatinine ratio.
Discontinuation
For patients who have achieved long-term remission, it is recommended to discontinue lithium gradually and in a controlled fashion.
Discontinuation symptoms may occur in patients stopping the medication including irritability, restlessness, and somatic symptoms like vertigo, dizziness, or lightheadedness. Symptoms occur within the first week and are generally mild and self-limiting within weeks.
Cluster Headaches, Migraine, and Hypnic Headache
Studies testing prophylactic use of lithium in cluster headaches (when compared to verapamil), migraine attacks, and hypnic headache indicate good efficacy.
Adverse Effects
The adverse effects of lithium include:
Very Common (> 10% incidence) Adverse Effects
Confusion
Constipation (usually transient, but can persist in some)
Decreased memory
Diarrhea (usually transient, but can persist in some)
Dry mouth
EKG changes – usually benign changes in T waves
Hand tremor (usually transient, but can persist in some) with an incidence of 27%. If severe, psychiatrist may lower lithium dosage, change lithium salt type or modify lithium preparation from long to short-acting (despite lacking evidence for these procedures) or use pharmacological help
Headache
Hyperreflexia — overresponsive reflexes
Leukocytosis — elevated white blood cell count
Muscle weakness (usually transient, but can persist in some)
Myoclonus — muscle twitching
Nausea (usually transient)
Polydipsia — increased thirst
Polyuria — increased urination
Renal (kidney) toxicity which may lead to chronic kidney failure, although some cases may be misattributed
Vomiting (usually transient, but can persist in some)
Vertigo
Common (1–10%) Adverse Effects
Acne
Extrapyramidal side effects — movement-related problems such as muscle rigidity, parkinsonism, dystonia, etc.
Euthyroid goitre — i.e. the formation of a goitre despite normal thyroid functioning
Hypothyroidism — a deficiency of thyroid hormone, though this condition is already common among patients with bipolar disorder.
Hair loss/hair thinning
Weight gain — 5% incidence, tends to start fast and then plateau. Usually ends at 1–2 kg.
Unknown Incidence
Sexual dysfunction Hypoglycaemia Glycosuria In addition to tremors, lithium treatment appears to be a risk factor for development of parkinsonism-like symptoms, although the causal mechanism remains unknown.
In the average bipolar patient, chronic lithium use is not associated with cognitive decline.
Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.
Hypothyroidism
The rate of hypothyroidism is around six times higher in people who take lithium. Low thyroid hormone levels in turn increase the likelihood of developing depression. People taking lithium thus should routinely be assessed for hypothyroidism and treated with synthetic thyroxine if necessary.
Because lithium competes with the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including amiloride and triamterene. It increases the appetite and thirst (“polydypsia”) and reduces the activity of thyroid hormone (hypothyroidism). The latter can be corrected by treatment with thyroxine and does not require the lithium dose to be adjusted. Lithium is also believed to cause renal dysfunction, although this does not appear to be common.
Lambert et al. (2016), comparing the rate of hypothyroidism in patients with bipolar disorder treated with 9 different medications, found that lithium users do not have a particularly high rate of hypothyroidism (8.8%) among BD patients – only 1.39 times the rate in oxcarbazepine users (6.3%). Lithium and quetiapine are not statistically different in terms of hypothyroidism rates. However, lithium users are tested much more frequently for hypothyroidism than those using other drugs. The authors write that there may be an element of surveillance bias in understanding lithium’s effects on the thyroid glands, as lithium users are tested 2.3-3.1 times as often. Furthermore, the authors argue that because hypothyroidism is common among BD patients regardless of lithium treatment, regular thyroid testing should be applied to all BD patients, not just those on lithium.
Pregnancy
Lithium is a teratogen, which can cause birth defects in a small number of newborns. Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defects including Ebstein’s anomaly if taken during pregnancy. Teratogenicity is affected by trimester and dose of Lithium. Most significantly affecting first-trimester cardiac development with greater effects at higher doses.
As the risks of stopping Lithium can be significant, patients are sometimes recommended to stay on this medicine while pregnant. Careful weighing of the risks and benefits should be made in consultation with a psychiatric physician.
For patients who are exposed to lithium, or plan to stay on the medication throughout their pregnancy, foetal echocardiography is routinely performed to monitor for cardiac anomalies.
While lithium is typically the most effective treatment, possible alternatives to Lithium include lamotrigine and second generation antipsychotics for the treatment of acute bipolar depression or for the management of bipolar patients with normal mood during pregnancy.
Breastfeeding
While only small amounts of Lithium are transmitted to the infant in breastmilk, there is limited data on the safety of Breastfeeding while on Lithium. Medical evaluation and monitoring of infants consuming breastmilk during maternal prescription may be indicated.
Kidney Damage
Lithium has been associated with several forms of kidney injury. It is estimated that impaired urinary concentrating ability is present in at least half of individuals on chronic lithium therapy, a condition called lithium-induced nephrogenic diabetes insipidus. Continued use of lithium can lead to more serious kidney damage in an aggravated form of diabetes insipidus. In rare cases, some forms of lithium-caused kidney damage may be progressive and lead to end-stage kidney failure with a reported incidence of 0.2% to 0.7%.
Some reports of kidney damage may be wrongly attributed to lithium, increasing the apparent rate of this adverse effect. Nielsen et al. (2018), citing 6 large observational studies since 2010, argue that findings of decreased kidney function are partially inflated by surveillance bias. Furthermore, modern data does not show that lithium increases the risk of end-stage kidney disease. Davis et al. (2018), using literature from a wider timespan (1977–2018), also found that lithium’s association with chronic kidney disease is unproven with various contradicting results. They also find contradicting results regarding end-stage kidney disease.
A 2015 nationwide study suggests that chronic kidney disease can be avoided by maintaining the serum lithium concentration at a level of 0.6–0.8 mmol/L and by monitoring serum creatinine every 3–6 months.
Hyperparathyroidism
Lithium-associated hyperparathyroidism is the leading cause of hypercalcemia in lithium-treated patients. Lithium may lead to exacerbation of pre-existing primary hyperparathyroidism or cause an increased set-point of calcium for parathyroid hormone suppression, leading to parathyroid hyperplasia.
Interactions
Lithium plasma concentrations are known to be increased with concurrent use of diuretics—especially loop diuretics (such as furosemide) and thiazides—and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Lithium concentrations can also be increased with concurrent use of ACE inhibitors such as captopril, enalapril, and lisinopril.
Lithium is primarily cleared from the body through glomerular filtration, but some is then reabsorbed together with sodium through the proximal tubule. Its levels are therefore sensitive to water and electrolyte balance. Diuretics act by lowering water and sodium levels; this causes more reabsorption of lithium in the proximal tubules so that the removal of lithium from the body is less, leading to increased blood levels of lithium. ACE inhibitors have also been shown in a retrospective case-control study to increase lithium concentrations. This is likely due to constriction of the afferent arteriole of the glomerulus, resulting in decreased glomerular filtration rate and clearance. Another possible mechanism is that ACE inhibitors can lead to a decrease in sodium and water. This will increase lithium reabsorption and its concentrations in the body.
Some drugs can increase the clearance of lithium from the body, which can result in decreased lithium levels in the blood. These drugs include theophylline, caffeine, and acetazolamide. Additionally, increasing dietary sodium intake may also reduce lithium levels by prompting the kidneys to excrete more lithium.
Lithium is known to be a potential precipitant of serotonin syndrome in people concurrently on serotonergic medications such as antidepressants, buspirone and certain opioids such as pethidine (meperidine), tramadol, oxycodone, fentanyl and others. Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.
High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported. Indeed, these and other antipsychotics have been associated with an increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.
Classical psychedelics such as psilocybin and LSD may cause seizures if taken while using lithium, although further research is needed.
Overdose
Lithium toxicity, which is also called lithium overdose and lithium poisoning, is the condition of having too much lithium in the blood. This condition also happens in persons who are taking lithium in which the lithium levels are affected by drug interactions in the body.
In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and diarrhoea, which may result in volume depletion. During acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness.
In chronic toxicity, people have primarily neurological symptoms which include nystagmus, tremor, hyperreflexia, ataxia, and change in mental status. During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific.
If the lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. If the toxicity is severe, lithium may need to be removed from the body.
Mechanism of Action
The specific biochemical mechanism of lithium action in stabilising mood is unknown.
Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis.
Unlike many other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations. Lithium may also increase the release of serotonin by neurons in the brain. In vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarisation compared to no lithium treatment and the same depolarisation.
Lithium both directly and indirectly inhibits GSK3β (glycogen synthase kinase 3β) which results in the activation of mTOR. This leads to an increase in neuroprotective mechanisms by facilitating the Akt signalling pathway. GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation. During mania, GSK-3β is activated via dopamine overactivity. GSK-3β inhibits the transcription factors β-catenin and cyclic AMP (cAMP) response element binding protein (CREB), by phosphorylation. This results in a decrease in the transcription of important genes encoding for neurotrophins. In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium. This hypothesis was supported by the low Ki of lithium for human pAp-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8–1 mM). The Ki of human pAp-phosphatase is ten times lower than that of GSK3β (glycogen synthase kinase 3β). Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3′-5′ phosphoadenosine phosphate), which was shown to inhibit PARP-1.
Another mechanism proposed in 2007 is that lithium may interact with nitric oxide (NO) signaling pathway in the central nervous system, which plays a crucial role in neural plasticity. The NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice. It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.
Lithium possesses neuroprotective properties by preventing apoptosis and increasing cell longevity.
Although the search for a novel lithium-specific receptor is ongoing, the high concentration of lithium compounds required to elicit a significant pharmacological effect leads mainstream researchers to believe that the existence of such a receptor is unlikely.
Oxidative Metabolism
Evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder. Oxidative stress and reduced levels of antioxidants (such as glutathione) lead to cell death. Lithium may protect against oxidative stress by up-regulating complexes I and II of the mitochondrial electron transport chain.
Dopamine and G-Protein Coupling
During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. Additionally, the post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder. Lithium treatment alters the function of certain subunits of the dopamine-associated G-protein, which may be part of its mechanism of action.
Glutamate and NMDA Receptors
Glutamate levels are observed to be elevated during mania. Lithium is thought to provide long-term mood stabilisation and have anti-manic properties by modulating glutamate levels. It is proposed that lithium competes with magnesium for binding to NMDA glutamate receptor, increasing the availability of glutamate in post-synaptic neurons, leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission. The NMDA receptor is also affected by other neurotransmitters such as serotonin and dopamine. Effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and cesium.
GABA Receptors
GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). Lithium has been shown to increase the level of GABA in plasma and cerebral spinal fluid. Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins. Lithium’s regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood-stabilising effects.
Cyclic AMP Secondary Messengers
Lithium’s therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms. The cyclic AMP secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor-coupled stimulation of cyclic AMP production. It is hypothesized that the dual effects of lithium are due to the inhibition of G-proteins that mediate cyclic AMP production. Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.
Inositol Depletion Hypothesis
Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in PIP2 synthesis. This leads to lower levels of inositol triphosphate, created by decomposition of PIP2. This effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction are affected by lithium. myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigate the function of SMIT. Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle.
Neurotrophic Factors
Lithium’s actions on Gsk3 result in activation of CREB, leading to higher expression of BDNF. (Valproate, another mood stabilizer, also increases the expression of BDNF.) As expected of increased BDNF expression, chronic lithium treatment leads to increased grey matter volume in brain areas implicated in emotional processing and cognitive control. Bipolar patients treated with lithium also have higher white matter integrity compared to those taking other drugs.
Lithium also increases the expression of mesencephalic astrocyte-derived neurotrophic factor (MANF), another neurotrophic factor, via the AP-1 transcription factor. MANF is able to regulate proteostasis by interacting with GRP78, a protein involved in the unfolded protein response.
Salts and product names Lithium carbonate (Li2CO3) is the most commonly used form of lithium salts, a carbonic acid involving the lithium element and a carbonate ion. Other lithium salts are also used as medication, such as lithium citrate (Li3C6H5O7), lithium sulfate, lithium chloride, and lithium orotate. Nanoparticles and microemulsions have also been invented as drug delivery mechanisms. As of 2020, there is a lack of evidence that alternate formulations or salts of lithium would reduce the need for monitoring serum lithium levels or lower systemic toxicity.
Tentative evidence in Alzheimer’s disease showed that lithium may slow progression. It has been studied for its potential use in the treatment of amyotrophic lateral sclerosis (ALS), but a study showed lithium had no effect on ALS outcomes.
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Asociality refers to the lack of motivation to engage in social interaction, or a preference for solitary activities. Asociality may be associated with avolition, but it can, moreover, be a manifestation of limited opportunities for social relationships. Developmental psychologists use the synonyms non-social, unsocial, and social uninterest. Asociality is distinct from, but not mutually exclusive to, anti-social behaviour. A degree of asociality is routinely observed in introverts, while extreme asociality is observed in people with a variety of clinical conditions.
Asociality is not necessarily perceived as a totally negative trait by society, since asociality has been used as a way to express dissent from prevailing ideas. It is seen as a desirable trait in several mystical and monastic traditions, notably in Hinduism, Jainism, Roman Catholicism, Eastern Orthodoxy, Buddhism and Sufism.
Introversion
Introversion is “the state of or tendency toward being wholly or predominantly concerned with and interested in one’s own mental life.” Introverted persons are considered the opposite of extraverts, who seem to thrive in social settings rather than being alone. An introvert may present as an individual preferring being alone or interacting with smaller groups over interaction with larger groups, writing over speaking, having fewer but more fulfilling friendships, and needing time for reflection. While not a measurable personality trait, some popular writers have characterised introverts as people whose energy tends to expand through reflection and dwindle during interaction.
In matters of the brain, researchers have found differences in anatomy between introverted and extraverted persons. Introverted people are found to experience a higher flow of blood to the frontal lobe than extraverts, which is the part of the brain that contributes to problem-solving, memory, and pre-emptive thought.
Social Anhedonia
Social anhedonia is found in both typical and extreme cases of asociality or personality disorders that feature social withdrawal. Social anhedonia is distinct from introversion and is frequently accompanied with alexithymia.
Many cases of social anhedonia are marked by extreme social withdrawal and the complete avoidance of social interaction. One research article studying the individual differences in social anhedonia discusses the negative aspects of this form of extreme or aberrant asociality. Some individuals with social anhedonia are at higher risk of developing schizophrenia and may have mental functioning that becomes poorer than the average
In Human Evolution and Anthropology
Scientific research suggests that asocial traits in human behaviour, personality, and cognition may have several useful evolutionary benefits. Traits of introversion and aloofness can protect an individual from impulsive and dangerous social situations because of reduced impulsivity and reward. Frequent voluntary seclusion stimulates creativity and can give the individual time to think, work, reflect, and see useful patterns more easily.
Research indicates the social and analytical functions of the brain function in a mutually exclusive way. With this in mind, researchers posit that people who devoted less time or interest to socialisation used the analytical part of the brain more frequently and thereby were often responsible for devising hunting strategies, creating tools, and spotting useful patterns in the environment in general for both their own safety and the safety of the group.
Imitation and social learning have been confirmed to be potentially limiting and maladaptive in animal and human populations. When social learning overrides personal experience (asocial learning), negative effects can be observed such as the inability to seek or pick the most efficient way to accomplish a task and a resulting inflexibility to changing environments. Individuals who are less receptible, motivated, and interested in sociability are likely less affected by or sensible to socially imitated information and faster to notice and react to changes in the environment, essentially holding onto their own observations in a rigid manner and, consequently, not imitating a maladaptive behaviour through social learning. These behaviours, including deficits in imitative behaviour, have been observed in individuals with autism spectrum disorders and introverts, and are correlated with the personality traits of neuroticism and disagreeableness.
The benefits of this behaviour for the individual and their kin caused it to be preserved in part of the human population. The usefulness for acute senses, novel discoveries, and critical analytical thought may have culminated in the preservation of the suspected genetic factors of autism and introversion itself due to their increased cognitive, sensorial, and analytical awareness.
In Psychopathology
Schizophrenia
In schizophrenia, asociality is one of the main five “negative symptoms”, with the others being avolition, anhedonia, reduced affect, and alogia. Due to a lack of desire to form relationships, social withdrawal is common in people with schizophrenia. People with schizophrenia may experience social deficits or dysfunction as a result of the disorder, leading to asocial behaviour. Frequent or ongoing delusions and hallucinations can deteriorate relationships and other social ties, isolating individuals with schizophrenia from reality and in some cases leading to homelessness. Even when treated with medication for the disorder, they may be unable to engage in social behaviours. These behaviours include things like maintaining conversations, accurately perceiving emotions in others, or functioning in crowded settings. There has been extensive research on the effective use of social skills training (SST) for the treatment of schizophrenia, in outpatient clinics as well as inpatient units. SST can be used to help patients with schizophrenia make better eye contact with other people, increase assertiveness, and improve their general conversational skills.
Personality Disorders
Avoidant Personality Disorder
Asociality is common amongst people with avoidant personality disorder (AvPD). They experience discomfort and feel inhibited in social situations, being overwhelmed by feelings of inadequacy. Such people remain consistently fearful of social rejection, choosing to avoid social engagements as they do not want to give people the opportunity to reject (or possibly, accept) them. Though they inherently crave a sense of belonging, their fear of criticism and rejection leads people with AvPD to actively avoid occasions that require social interaction, leading to extremely asocial tendencies; as a result, these individuals often have difficulty cultivating and preserving close relationships.
People with AvPD may also display social phobia, the difference being that social phobia is the fear of social circumstances whereas AvPD is better described as an aversion to intimacy in relationships.
Schizoid Personality Disorder
Schizoid personality disorder (SzPD) is characterised by a lack of interest in social relationships, a tendency towards a solitary lifestyle, secretiveness, emotional coldness, and apathy. Affected individuals may simultaneously demonstrate a rich and elaborate but exclusively internal fantasy world.
It is not the same as schizophrenia, although they share such similar characteristics as detachment and blunted affect. There is, moreover, increased prevalence of the disorder in families with schizophrenia.
Schizotypal Personality Disorder
Schizotypal personality disorder is characterized by a need for social isolation, anxiety in social situations, odd behaviour and thinking, and often unconventional beliefs. People with this disorder feel extreme discomfort with maintaining close relationships with people, and therefore they often do not. People who have this disorder may display peculiar manners of talking and dressing and often have difficulty in forming relationships. In some cases, they may react oddly in conversations, not respond, or talk to themselves.
Autism
Autistic people may display profoundly asocial tendencies, due to differences in how autistic and allistic (non-autistic) people communicate. These different communication styles can cause mutual friction between the two neurotypes, known as the double empathy problem. Autistic people tend to express emotions differently and less intensely than allistic people, and often do not pick up on allistic social cues or linguistic pragmatics (including eye contact, facial expressions, tone of voice, body language, and implicatures) used to convey emotions and hints.
Connecting with others is important to overall health. An increased difficulty in accurately reading social cues by others can affect this desire for people with autism. The risk of adverse social experiences is high for those with autism, and so they may prefer to be avoidant in social situations rather than experience anxiety over social performance. Social deficits in people with autism is directly correlated with the increased prevalence of social anxiety in this community. As they are in a steep minority, there is risk of not having access to like-minded peers in their community, which can lead them to withdrawal and social isolation.
Mood Disorders
Depression
Asociality can be observed in individuals with major depressive disorder or dysthymia, as individuals lose interest in everyday activities and hobbies they used to enjoy, this may include social activities, resulting in social withdrawal and withdrawal tendencies.
SST can be adapted to the treatment of depression with a focus on assertiveness training. Depressed patients often benefit from learning to set limits with others, to obtain satisfaction for their own needs, and to feel more self-confident in social interactions. Research suggests that patients who are depressed because they tend to withdraw from others can benefit from SST by learning to increase positive social interactions with others instead of withdrawing from social interactions.
Social Anxiety Disorder
Asocial behaviour is observed in people with social anxiety disorder (SAD), who experience perpetual and irrational fears of humiliating themselves in social situations. They often have panic attacks and severe anxiety as a result, which can occasionally lead to agoraphobia. The disorder is common in children and young adults, diagnosed on average between the ages of 8 and 15. If left untreated, people with SAD exhibit asocial behaviour into adulthood, avoiding social interactions and career choices that require interpersonal skills. SST can help people with social phobia or shyness to improve their communication and social skills so that they will be able to mingle with others or go to job interviews with greater ease and self-confidence.
Traumatic Brain Injury
Traumatic brain injuries (TBI) can also lead to asociality and social withdrawal.
Management
Treatments
Social Skills Training
Social skills training (SST) is an effective technique aimed towards anyone with “difficulty relating to others,” a common symptom of shyness, marital and family conflicts, or developmental disabilities; as well as of many mental and neurological disorders including adjustment disorders, anxiety disorders, attention-deficit/hyperactivity disorder, social phobia, alcohol dependence, depression, bipolar disorder, schizophrenia, avoidant personality disorder, paranoid personality disorder, obsessive-compulsive disorder, and schizotypal personality disorder.
Fortunately for people who display difficulty relating to others, social skills can be learned, as they are not simply inherent to an individual’s personality or disposition. Therefore, there is hope for anyone who wishes to improve their social skills, including those with psychosocial or neurological disorders. Nonetheless, it is important to note that asociality may still be considered neither a character flaw nor an inherently negative trait.
SST includes improving eye contact, speech duration, frequency of requests, and the use of gestures, as well as decreasing automatic compliance to the requests of others. SST has been shown to improve levels of assertiveness (positive and negative) in both men and women.
Additionally, SST can focus on receiving skills (e.g. accurately perceiving problem situations), processing skills (e.g. considering several response alternatives), and sending skills (delivering appropriate verbal and non-verbal responses).
Metacognitive Interpersonal Therapy
Metacognitive interpersonal therapy is a method of treating and improving the social skills of people with personality disorders that are associated with asociality. Through metacognitive interpersonal therapy, clinicians seek to improve their patients’ metacognition, meaning the ability to recognise and read the mental states of themselves. The therapy differs from SST in that the patient is trained to identify their own thoughts and feelings as a means of recognising similar emotions in others. Metacognitive interpersonal therapy has been shown to improve interpersonal and decision-making skills by encouraging awareness of suppressed inner states, which enables patients to better relate to other people in social environments.
The therapy is often used to treat patients with two or more co-occurring personality disorders, commonly including obsessive-compulsive and avoidant behaviours.
Coping Mechanisms
In order to cope with asocial behaviour, many individuals, especially those with avoidant personality disorder, develop an inner world of fantasy and imagination to entertain themselves when feeling rejected by peers. Asocial people may frequently imagine themselves in situations where they are accepted by others or have succeeded at an activity. Additionally, they may have fantasies relating to memories of early childhood and close family members.
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Common side effects include sleepiness, movement disorders, nausea, and diarrhoea. Serious side effects are valid for all atypical antipsychotics and may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, angioedema, and high blood sugar levels, although lurasidone is less likely to cause high blood sugar levels in most patients, hyperosmolar hyperglycaemic syndrome may occur. In older people with psychosis as a result of dementia, it may increase the risk of dying. Use during pregnancy is of unclear safety.
Lurasidone was first approved for medical use in the United States in 2010. In 2013, it was approved in Canada, and by the United States Food and Drug Administration, to treat bipolar depression, either as monotherapy or adjunctively with lithium or valproate. Generic versions were approved in the United States in 2019, and became available in 2023. In 2020, it was the 259th most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Brief History
Lurasidone was first synthesised circa 2003.
Lurasidone is a structural analogue of ziprasidone. Lurasidone shows a very close pharmacological profile and has been synthesized similarly to ziprasidone.
Lurasidone is chemically similar to perospirone (also a chemical analogue of ziprasidone), as well as risperidone, paliperidone and iloperidone.
It has approval from the US Food and Drug Administration (FDA) for treating schizophrenia since 2010, and for treating depressive episodes in adults with bipolar I disorder since 2013.
Medical Uses
Lurasidone is used to treat schizophrenia and bipolar disorder. In bipolar disorder, It has been studied both as a monotherapy and adjunctive treatment to lithium or valproate.
The European Medicines Agency approved lurasidone for the treatment of schizophrenia for people aged 13 years and older, but not for bipolar disorder. In the United States, it is used to treat schizophrenia for people aged 13 years and older, as well as depressive episodes of bipolar disorder age 10 and over as a monotherapy, and in conjunction with lithium or valproate in adults.
In July 2013, lurasidone received approval for bipolar I depression.
In June 2020, lurasidone was approved in Japan, eight years after its first approval in the United States. In Japan it is approved for bipolar depression and schizophrenia.
Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine, olanzapine and possibly asenapine) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity, which is yet to be clearly demonstrated for lurasidone.
In the early post approval period lurasidone-treated patients with bipolar disorder were retrospectively found to have more complex clinical profiles, comorbidities, and prior treatment history compared to patients initiated with other atypical antipsychotics. The study authors suggest this may be due to:
“the overall clinical profile of lurasidone, the role perceived for lurasidone in the therapeutic armamentarium by practitioners, and the recent introduction of lurasidone into clinical practice during the study period.”
Lurasidone is not approved by the FDA for the treatment of behaviour disorders in older adults with dementia.
Contraindications
Lurasidone is contraindicated in individuals who are taking strong inhibitors of the liver enzyme CYP3A4 (ketoconazole, clarithromycin, ritonavir, levodropropizine, etc.) or inducers (carbamazepine, St. John’s wort, phenytoin, rifampicin etc.). The use of lurasidone in pregnant women has not been studied and is not recommended; in animal studies, no risks have been found. Excretion in breast milk is also unknown; lurasidone is not recommended for breastfeeding women. In the United States it is not indicated for use in children. The enzyme CYP3A4 is involved in the digestion of drugs. Inhibitors such as grapefruit juice block its function resulting in too much drug in the body.
Side Effects
Side effects are generally similar to other antipsychotics. The drug has a relatively well tolerated side effect profile, with low propensity for QTc interval changes, weight gain and lipid-related adverse effects. In a 2013 meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to produce the second least (after haloperidol) weight gain, the least QT interval prolongation, the fourth most extrapyramidal side effects (after haloperidol, zotepine and chlorpromazine) and the sixth least sedation (after paliperidone, sertindole, amisulpride, iloperidone, and aripiprazole).
As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack; however, these risks are not likely to be greater than those associated with antipsychotics of other classes. Similarly, lurasidone should not be used to treat dementia-related psychosis, as evidence has shown increased mortality with antipsychotic use.
Weight gain is reported in up to 15% and 16% of users. Other possible side effects include vomiting, akathisia, dystonia, parkinsonism, somnolence, dizziness, sedation and nausea.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Interactions
Blood plasma concentrations may be increased when combined with CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir, and voriconazole) possibly leading to more side effects. This has been clinically verified for ketoconazole, which increases lurasidone exposure by a factor of 9, and is also expected for other 3A4 inhibitors such as grapefruit juice. Co-administration of CYP3A4 inducers like rifampicin, carbamazepine or St. John’s wort can reduce plasma levels of lurasidone and its active metabolite, and consequently decrease the effects of the drug. For rifampicin, the reduction was sixfold in a study.
Pharmacology
Pharmacodynamics
Lurasidone [(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl) piperazin-1-ylmethyl]-cyclohexylmethyl}-hexahydro-4,7-methano-2Hisoindole-1,3-dione hydrochloride]] is an azapirone derivative and acts as an antagonist of the dopamine D2 and D3 receptors, and the serotonin5-HT2A and 5-HT7 receptors, and the α2C-adrenergic receptor, and as a partial agonist of the serotonin 5-HT1A receptor. It has moderate-affinity antagonism at α2C-adrenergic receptors; low to very low-affinity antagonism at α1A-adrenergic α2A-adrenergic receptors.
It has only low and likely clinically unimportant affinity for the serotonin 5-HT2C receptor, which may underlie its low propensity for appetite stimulation and weight gain. The drug also has negligible affinity for the histamine H1 receptor and the muscarinic acetylcholine receptors, and hence has no antihistamine or anticholinergic effects. Drowsiness (somnolence) side effect is not explained by its antagonist activity to histamine.
The relationship between dose and D2 receptor occupancy levels were 41–43% for 10 mg, 51–55% for 20 mg, 63–67% for 40 mg, 77–84% for 60 mg, and 73–79% for 80 mg.
Pharmacokinetics
Lurasidone is taken by mouth and has an estimated absorption rate of 9 to 19%. Studies have shown that when lurasidone is taken with food, absorption increases about twofold. Peak blood plasma concentrations are reached after one to three hours. About 99% of the circulating substance are bound to plasma proteins. Efficacy data for lurasidone have been evaluated for doses of 20 mg to 120 mg daily
Lurasidone is extensively metabolised by CYP3A4 leading to contraindication of both strong inhibitors as well as strong inducers of this enzyme, but has negligible affinity to other cytochrome P450 enzymes. It is transported by P-glycoprotein and ABCG2 and also inhibits these carrier proteins in vitro. It also inhibits the solute carrier protein SLC22A1, but no other relevant transporters.
Main metabolism pathways are oxidative N-dealkylation between the piperazine and cyclohexane rings, hydroxylation of the norbornane ring, and S-oxidation. Other pathways are hydroxylation of the cyclohexane ring and reductive cleavage of the isothiazole ring followed by S-methylation. The two relevant active metabolites are the norbornane hydroxylation products called ID-14283 and ID-14326, the former reaching pharmacologically relevant blood plasma concentrations. The two major inactive metabolites are the N-dealkylation products (the carboxylic acid ID-20219 and the piperazine ID-11614), and a norbornane hydroxylated derivative of ID-20219 (ID-20220). Of lurasidone and its metabolites circulating in the blood, the native drug makes up 11%, the main active metabolite 4%, and the inactive carboxylic acids 24% and 11%, respectively. Several dozen metabolites have been identified altogether.
Biological half-life is given as 18 hours or 20 to 40 hours in different sources. 80% or 67% of a radiolabelled dose was recovered from the faeces, and 9% or 19% from the urine.
Society and Culture
Cost
In Canada, as of 2014, lurasidone is generally more expensive than risperidone and quetiapine but less expensive than aripiprazole.
In the US, because a number of doses have the same price per tablet, pill splitting has been used to decrease costs. In 2019, generic versions were approved in the United States; however, they only became available in 2023 due to drug patents.
Brand Names
In India, this drug is available under the brand names of Atlura, Lurace, Lurafic, Luramax (Sun Pharma), Lurasid, Lurastar, Latuda, Lurata and additionally as Alsiva, Emsidon, Lurakem, Luratrend, Tablura, and Unison.
Regulatory Approval
Lurasidone was approved in the United States for the treatment of schizophrenia in October 2010 and for the treatment of depressive episodes associated with bipolar I disorder in June 2013. It received regulatory approval in the United Kingdom in September 2014. In October 2014, NHS Scotland advised use of lurasidone for schizophrenic adults who have not seen improvements with previous antipsychotics due to problems that arise from weight gain or changes in metabolic pathways when taking other medications. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion for it in January 2014, and it was approved for medical use by the EMA in March 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on 15 October 2012. European Commission has granted a marketing authorization for once-daily oral lurasidone for the treatment of schizophrenia in adults. It is approved for use in the EU.
Generic versions of lurasidone were approved for use in the United States in January 2019 and became available in 2023.
This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Lurasidone >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder as well as the medium to long-term management of bipolar disorder.
It was initially approved in the United States in 2009 and approved as a generic medication in 2020.
Medical Uses
Asenapine has been approved by the FDA (US Food and Drug Administration) for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. In Australia asenapine’s approved (and also listed on the PBS (Pharmaceutical Benefits Scheme)) indications include the following.
Schizophrenia
Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder
Maintenance treatment, as monotherapy, of bipolar I disorder
In the European Union and the United Kingdom, asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.
Asenapine is absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed. A transdermal formulation of asenapine was approved in the United States in October 2019 under the brand name Secuado.
Schizophrenia
A Cochrane systematic review found that while Asenapine has some preliminary evidence that it improves positive, negative, and depressive symptoms, it does not have enough research to merit a certain recommendation of asenapine for the treatment of schizophrenia.
Bipolar Disorder
For the medium-term and long-term management and control of both depressive and manic features of bipolar disorder asenapine was found be equally effective as olanzapine, but with a substantially superior side effect profile.
In acute mania, asenapine was found to be significantly superior to placebo. As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs such as risperidone and olanzapine (with the exception of ziprasidone). Drop-out rates (in clinical trials) were also unusually high with asenapine. According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes.
Adverse Effects
Adverse Effect Incidence
Very common (>10% incidence) adverse effects include:
Somnolence
Common (1-10% incidence) adverse effects include:
Weight gain
Increased appetite
Extrapyramidal side effects (EPS; such as dystonia, akathisia, dyskinesia, muscle rigidity, parkinsonism)
Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate)
Tardive dyskinesia
Speech disturbance
Rhabdomyolysis
Angioedema
Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia
Accommodation disorder[clarification needed]
Pulmonary embolism
Gynaecomastia
Galactorrhoea
Unknown incidence adverse effects:
Allergic reaction
Restless legs syndrome
Nausea
Oral mucosal lesions (ulcerations, blistering and inflammation)
Salivary hypersecretion
Hyperprolactinaemia
Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and a 2013 meta-analysis found significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22).
Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis. This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic. The same meta-analysis suggested that asenapine had a relatively high risk of extrapyramidal symptoms compared to other atypical antipsychotics but a lower risk than first-generation or typical antipsychotics.
Discontinuation
For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a transient withdrawal symptom. It may also result in recurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Pharmacology
Pharmacodynamics
Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors. At all other targets asenapine is an antagonist.
Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors.
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The dopamine transporter (DAT) also (sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in the human by the SLC6A3 gene, (also known as DAT1), that pumps the neurotransmitterdopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.
DAT is implicated in a number of dopamine-related disorders, including attention deficit hyperactivity disorder, bipolar disorder, clinical depression, eating disorders, and substance use disorders. The gene that encodes the DAT protein is located on chromosome 5, consists of 15 coding exons, and is roughly 64 kbp long. Evidence for the associations between DAT and dopamine related disorders has come from a type of genetic polymorphism, known as a variable number tandem repeat, in the SLC6A3 gene, which influences the amount of protein expressed.
Function
DAT is an integral membrane protein that removes dopamine from the synaptic cleft and deposits it into surrounding cells, thus terminating the signal of the neurotransmitter. Dopamine underlies several aspects of cognition, including reward, and DAT facilitates regulation of that signal.
Mechanism
DAT is a symporter that moves dopamine across the cell membrane by coupling the movement to the energetically-favourable movement of sodium ions moving from high to low concentration into the cell. DAT function requires the sequential binding and co-transport of two Na+ ions and one Cl− ion with the dopamine substrate. The driving force for DAT-mediated dopamine reuptake is the ion concentration gradient generated by the plasma membrane Na+/K+ ATPase.
In the most widely accepted model for monoamine transporter function, sodium ions must bind to the extracellular domain of the transporter before dopamine can bind. Once dopamine binds, the protein undergoes a conformational change, which allows both sodium and dopamine to unbind on the intracellular side of the membrane.
Studies using electrophysiology and radioactive-labelled dopamine have confirmed that the dopamine transporter is similar to other monoamine transporters in that one molecule of neurotransmitter can be transported across the membrane with one or two sodium ions. Chloride ions are also needed to prevent a build-up of positive charge. These studies have also shown that transport rate and direction is totally dependent on the sodium gradient.
Because of the tight coupling of the membrane potential and the sodium gradient, activity-induced changes in membrane polarity can dramatically influence transport rates. In addition, the transporter may contribute to dopamine release when the neuron depolarises.
DAT–Cav Coupling
Preliminary evidence suggests that the dopamine transporter couples to L-type voltage-gated calcium channels (particularly Cav1.2 and Cav1.3), which are expressed in virtually all dopamine neurons. As a result of DAT–Cav coupling, DAT substrates that produce depolarising currents through the transporter are able to open calcium channels that are coupled to the transporter, resulting in a calcium influx in dopamine neurons. This calcium influx is believed to induce CAMKII-mediated phosphorylation of the dopamine transporter as a downstream effect; since DAT phosphorylation by CAMKII results in dopamine efflux in vivo, activation of transporter-coupled calcium channels is a potential mechanism by which certain drugs (e.g. amphetamine) trigger neurotransmitter release.
Protein Structure
The initial determination of the membrane topology of DAT was based upon hydrophobic sequence analysis and sequence similarities with the GABA transporter. These methods predicted twelve transmembrane domains (TMD) with a large extracellular loop between the third and fourth TMDs. Further characterisation of this protein used proteases, which digest proteins into smaller fragments, and glycosylation, which occurs only on extracellular loops, and largely verified the initial predictions of membrane topology. The exact structure of the Drosophila melanogaster dopamine transporter (dDAT) was elucidated in 2013 by X-ray crystallography.
Location and Distribution
Regional distribution of DAT has been found in areas of the brain with established dopaminergic circuitry, including the nigrostriatal, mesolimbic, and mesocortical pathways. The nuclei that make up these pathways have distinct patterns of expression. Gene expression patterns in the adult mouse show high expression in the substantia nigra pars compacta.
DAT in the mesocortical pathway, labelled with radioactive antibodies, was found to be enriched in dendrites and cell bodies of neurons in the substantia nigra pars compacta and ventral tegmental area. This pattern makes sense for a protein that regulates dopamine levels in the synapse.
Staining in the striatum and nucleus accumbens of the mesolimbic pathway was dense and heterogeneous. In the striatum, DAT is localized in the plasma membrane of axon terminals. Double immunocytochemistry demonstrated DAT colocalisation with two other markers of nigrostriatal terminals, tyrosine hydroxylase and D2dopamine receptors. The latter was thus demonstrated to be an autoreceptor on cells that release dopamine. TAAR1 is a presynaptic intracellular receptor that is also colocalised with DAT and which has the opposite effect of the D2 autoreceptor when activated; i.e. it internalises dopamine transporters and induces efflux through reversed transporter function via PKA and PKC signalling.
Surprisingly, DAT was not identified within any synaptic active zones. These results suggest that striatal dopamine reuptake may occur outside of synaptic specializations once dopamine diffuses from the synaptic cleft.
In the substantia nigra, DAT is localised to axonal and dendritic (i.e. pre- and post-synaptic) plasma membranes.
Within the perikarya of pars compacta neurons, DAT was localised primarily to rough and smooth endoplasmic reticulum, Golgi complex, and multivesicular bodies, identifying probable sites of synthesis, modification, transport, and degradation.
Genetics and Regulation
The gene for DAT, known as DAT1, is located on chromosome 5p15. The protein encoding region of the gene is over 64 kb long and comprises 15 coding segments or exons. This gene has a variable number tandem repeat (VNTR) at the 3’ end (rs28363170) and another in the intron 8 region. Differences in the VNTR have been shown to affect the basal level of expression of the transporter; consequently, researchers have looked for associations with dopamine-related disorders.
Nurr1, a nuclear receptor that regulates many dopamine-related genes, can bind the promoter region of this gene and induce expression. This promoter may also be the target of the transcription factor Sp-1.
While transcription factors control which cells express DAT, functional regulation of this protein is largely accomplished by kinases. MAPK, CAMKII, PKA, and PKC can modulate the rate at which the transporter moves dopamine or cause the internalisation of DAT. Co-localised TAAR1 is an important regulator of the dopamine transporter that, when activated, phosphorylates DAT through protein kinase A (PKA) and protein kinase C (PKC) signalling. Phosphorylation by either protein kinase can result in DAT internalisation (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux). Dopamine autoreceptors also regulate DAT by directly opposing the effect of TAAR1 activation.
The human dopamine transporter (hDAT) contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro. In contrast, the human serotonin transporter (hSERT) and human norepinephrine transporter (hNET) do not contain zinc binding sites. Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of attention deficit hyperactivity disorder.
Biological Role and Disorders
The rate at which DAT removes dopamine from the synapse can have a profound effect on the amount of dopamine in the cell. This is best evidenced by the severe cognitive deficits, motor abnormalities, and hyperactivity of mice with no dopamine transporters. These characteristics have striking similarities to the symptoms of ADHD.
Differences in the functional VNTR have been identified as risk factors for bipolar disorder and ADHD. Data has emerged that suggests there is also an association with stronger withdrawal symptoms from alcoholism, although this is a point of controversy. An allele of the DAT gene with normal protein levels is associated with non-smoking behaviour and ease of quitting. Additionally, male adolescents particularly those in high-risk families (ones marked by a disengaged mother and absence of maternal affection) who carry the 10-allele VNTR repeat show a statistically significant affinity for antisocial peers.
Increased activity of DAT is associated with several different disorders, including clinical depression.
Mutations in DAT have been shown to cause dopamine transporter deficiency syndrome, an autosomal recessive movement disorder characterised by progressively worsening dystonia and parkinsonism.
Pharmacology
The dopamine transporter is the target of substrates, dopamine releasers, transport inhibitors and allosteric modulators.
Cocaine blocks DAT by binding directly to the transporter and reducing the rate of transport. In contrast, amphetamine enters the presynaptic neuron directly through the neuronal membrane or through DAT, competing for reuptake with dopamine. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine binds to TAAR1, it reduces the firing rate of the postsynaptic neuron and triggers protein kinase A and protein kinase C signalling, resulting in DAT phosphorylation. Phosphorylated DAT then either operates in reverse or withdraws into the presynaptic neuron and ceases transport. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol. Amphetamine also produces dopamine efflux through a second TAAR1-independent mechanism involving CAMKIIα-mediated phosphorylation of the transporter, which putatively arises from the activation of DAT-coupled L-type calcium channels by amphetamine.
The dopaminergic mechanisms of each drug are believed to underlie the pleasurable feelings elicited by these substances.
Interactions
Dopamine transporter has been shown to interact with:
Alpha-synuclein
PICK1
TGFB1I1
Apart from these innate protein-protein interactions, recent studies demonstrated that viral proteins such as HIV-1 Tat protein interacts with the DAT and this binding may alter the dopamine homeostasis in HIV positive individuals which is a contributing factor for the HIV-associated neurocognitive disorders.
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The study is investigating possible differences between people with a diagnosis of bipolar disorder and people without the diagnosis. In particular it is investigating difference in cognition and brain structure/function.
The Maudsley Study of bipolar disorder investigates different aspects of thinking, such as memory and attention, in twins with and without bipolar disorder. The tasks participants complete involve defining words and solving different kinds of problems. With adequate numbers of twins participating in the study, the hope is to understand any differences between these two groups. The eventual aim is to increase understanding of this complex mood disorder and to enhance future therapies for it.
This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Maudsley_Bipolar_Twin_Study >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressive disorder (MDD), tic disorders and irritability associated with autism. It is taken by mouth or injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.
In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.
Common side effects include vomiting, constipation, sleepiness, dizziness, weight gain and movement disorders. Serious side effects may include neuroleptic malignant syndrome, tardive dyskinesia and anaphylaxis. It is not recommended for older people with dementia-related psychosis due to an increased risk of death. In pregnancy, there is evidence of possible harm to the baby. It is not recommended in women who are breastfeeding. It has not been very well studied in people less than 18 years old. The exact mode of action is not entirely clear but may involve effects on dopamine and serotonin.
Aripiprazole was approved for medical use in the United States in 2002. It is available as a generic medication. In 2019, it was the 101st most commonly prescribed medication in the United States, with more than 6 million prescriptions. Aripiprazole was discovered in 1988 by scientists at the Japanese firm Otsuka Pharmaceutical.
Aripiprazole was discovered by scientists at Otsuka Pharmaceutical and was called OPC-14597. It was first published in 1995. Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.
It was approved by the US Food and Drug Administration (FDA) for schizophrenia in November 2002, and the European Medicines Agency in June 2004; for acute manic and mixed episodes associated with bipolar disorder on 01 October 2004; as an adjunct for major depressive disorder on 20 November 2007; and to treat irritability in children with autism on 20 November 2009. Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.
Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years.
In 2006, the FDA required manufacturers to add a black box warning to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.
In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication. That same year, BMS settled a case with the US government in which it paid $515 million; the case covered several drugs but the focus was on BMS’s off-label marketing of aripiprazole for children and older people with dementia.
In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of apripiprazole.
As of 2013, Abilify had annual sales of US$7 billion. In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug. Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole.
Otsuka’s US patent on aripiprazole expired on 20 October 2014, but due to a paediatric extension, a generic did not become available until 20 April 2015. Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007. On 15 November 2010, this challenge was rejected by the US District Court in New Jersey.
Otsuka’s European patent EP0367141 which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014. The UK Intellectual Property Office decided on 04 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015.
From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.
In April 2015, the FDA announced the first generic versions. In October 2015, aripiprazole lauroxil, a prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA.
In 2016, BMS settled cases with 42 US states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.
In November 2017, the FDA approved Abilify MyCite, a digital pill containing a sensor intended to record when its consumer takes their medication.
Medical Uses
Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.
Schizophrenia
The 2016 NICE guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second line treatment after risperidone for people between 15 and 17 who are having an acute exacerbation or recurrence of psychosis or schizophrenia. A 2014 NICE review of the depot formulation of the drug found that it might have a role in treatment as an alternative to other depot formulations of second generation antipsychotics for people who have trouble taking medication as directed or who prefer it.
A 2014 Cochrane review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor. A 2011 Cochrane review comparing aripiprazole with placebo concluded that high dropout rates in clinical trials, and a lack of outcome data regarding general functioning, behaviour, mortality, economic outcomes, or cognitive functioning make it difficult to definitively conclude that aripiprazole is useful for the prevention of relapse. A Cochrane review found only low quality evidence of effectiveness in treating schizophrenia. Accordingly, part of its methodology on quality of evidence is based on quantity of qualified studies.
A 2013 review found that it is in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine and slightly more effective than ziprasidone, chlorpromazine, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for weight gain, 5th best for extrapyramidal symptoms, best for prolactin elevation, 2nd best for QTc prolongation, and 5th best for sedation). The authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.
In 2013 the World Federation of Societies for Biological Psychiatry recommended aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A.
The British Association for Psychopharmacology similarly recommends that all persons presenting with psychosis receive treatment with an antipsychotic, and that such treatment should continue for at least 1-2 years, as “There is no doubt that antipsychotic discontinuation is strongly associated with relapse during this period”. The guideline further notes that “Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the recommended range (Evidence level A)”.
The British Association for Psychopharmacology and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on each person’s preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics
Bipolar Disorder
Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents. Used as maintenance therapy, it is useful for the prevention of manic episodes, but is not useful for bipolar depression. Thus, it is often used in combination with an additional mood stabiliser; however, co-administration with a mood stabiliser increases the risk of extrapyramidal side effects.
Major Depression
Aripiprazole is an effective add-on treatment for major depressive disorder; however, there is a greater rate of side effects such as weight gain and movement disorders. The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning. Aripiprazole may interact with some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). There are interactions with fluoxetine and paroxetine and lesser interactions with sertraline, escitalopram, citalopram, and fluvoxamine, which inhibit CYP2D6, for which aripiprazole is a substrate. CYP2D6 inhibitors increase aripiprazole concentrations to 2-3 times their normal level.
Autism
Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours. Adverse effects include weight gain, sleepiness, drooling and tremors. It is suggested that children and adolescents need to be monitored regularly while taking this medication, to evaluate if this treatment option is still effective after long-term use and note if side effects are worsening. Further studies are needed to understand if this drug is helpful for children after long term use.
Tic Disorders
Aripiprazole is approved for the treatment of Tourette’s syndrome. It is effective, safe, and well-tolerated for this use per systematic reviews and meta-analyses
Obsessive-Compulsive Disorder
A 2014 systematic review and meta-analysis concluded that add-on therapy with low dose aripiprazole is an effective treatment for obsessive-compulsive disorder (OCD) that does not improve with selective serotonin reuptake inhibitors (SSRIs) alone. The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms. Risperidone, another second-generation antipsychotic, appears to be superior to aripiprazole for this indication, and is recommended by the 2007 American Psychiatric Association guidelines. However, aripiprazole is cautiously recommended by a 2017 review on antipsychotics for OCD. Aripiprazole is not currently approved for the treatment of OCD and is instead used off-label for this indication.
Adverse Effects
In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.
Uncontrolled movement such as restlessness, tremors, and muscle stiffness may occur.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Overdose
Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these people were elevated by up to 3-4 fold over normal therapeutic levels; as of 2008 no deaths had been recorded.
Interactions
Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.
Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose.
Antipsychotics like aripiprazole and stimulant medications, such as amphetamine, are traditionally thought to have opposing effects to their effects on dopamine receptors: stimulants are thought to increase dopamine in the synaptic cleft, whereas antipsychotics are thought to decrease dopamine. However, it is an oversimplification to state the interaction as such, due to the differing actions of antipsychotics and stimulants in different parts of the brain, as well as the effects of antipsychotics on non-dopaminergic receptors. This interaction frequently occurs in the setting of comorbid attention-deficit hyperactivity disorder (ADHD) (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has been reported to provide some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.
Pharmacology
Pharmacodynamics
Aripiprazole’s mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). It shows differential engagement at the dopamine receptor (D2). It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors, D3, and partially D4 and is a partial activator of serotonin (5-HT1A, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7). It also shows lower and likely insignificant effect on histamine (H1), epinephrine/norepinephrine (α), and otherwise dopamine (D4), as well as the serotonin transporter. Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.
As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D2 partial agonist (with an intrinsic activity of ~25%) as being similar to a full agonist but at a reduced level of activity presents a misleading oversimplification of its actions; for example, among other effects, aripiprazole has been shown, in vitro, to bind to and/or induce receptor conformations (i.e. facilitate receptor shapes) in such a way as to not only prevent receptor internalisation (and, thus, lower receptor density) but even to lower the rate of receptor internalisation below that of neurons not in the presence of agonists (including dopamine) or antagonists. It is often the nature of partial agonists, including aripiprazole, to display a stabilising effect (such as on mood in this case) with agonistic activity when there are low levels of endogenous neurotransmitters (such as dopamine) and antagonistic activity in the presence of high levels of agonists associated with events such as mania, psychosis, and drug use. In addition to aripiprazole’s partial agonism and functional selectivity characteristics, its effectiveness may be mediated by its very high dopamine D2 receptor occupancy (approximately 32%, 53%, 72%, 80%, and 97% at daily dosages of 0.5 mg, 1 mg, 2 mg, 10 mg, and 40 mg respectively) as well as balanced selectivity for pre- and postsynaptic receptors (as suggested by its equal affinity for both D2S and D2L receptor forms). Aripiprazole has been characterised as possessing predominantly antagonistic activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors; however, while this explanation intuitively explains the drug’s efficacy as an antipsychotic, as degree of agonism is a function of more than a drug’s inherent properties as well as in vitro demonstration of aripiprazole’s partial agonism in cells expressing postsynaptic (D2L) receptors, it was noted that “It is unlikely that the differential actions of aripiprazole as an agonist, antagonist, or partial agonist were entirely due to differences in relative D2 receptor expression since aripiprazole was an antagonist in cells with the highest level of expression (4.6 pmol/mg) and a partial agonist in cells with an intermediate level of expression (0.5-1 pmol/mg). Instead, the current data are most parsimoniously explained by the ‘functional selectivity’ hypothesis of Lawler et al (1999)”. Aripiprazole is also a partial agonist of the D3 receptor. In healthy human volunteers, D2 and D3 receptor occupancy levels are high, with average levels ranging between approximately 71% at 2 mg/day to approximately 96% at 40 mg/day. Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.
Aripiprazole is also a partial agonist of the serotonin 5-HT1A receptor (intrinsic activity = 68%). Casting doubt on the significance of aripiprazole’s agonism of 5-HT1A receptors, a PET scan study of 12 patients receiving doses ranging from 10 to 30 mg found 5-HT1A receptor occupancy to be only 16% compared to ~90% for D2. It is a very weak partial agonist of the 5-HT2A receptor (intrinsic activity = 12.7%), and like other atypical antipsychotics, displays a functional antagonist profile at this receptor. The drug differs from other atypical antipsychotics in having higher affinity for the D2 receptor than for the 5-HT2A receptor. At the 5-HT2B receptor, aripiprazole has both great binding affinity and acts as a potent inverse agonist, “Aripiprazole decreased PI hydrolysis from a basal level of 61% down to a low of 30% at 1000 nM, with an EC50 of 11 nM”. Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the 5-HT2C receptor (intrinsic activity = 82%) and with relatively weak affinity; this property may underlie the minimal weight gain seen in the course of therapy. At the 5-HT7 receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor. Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites, such as the histamine H1, α-adrenergic, and dopamine D4 receptors as well as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors.
Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g. at 5-HT6 and D2L), sometimes an inverse agonist (e.g. 5-HT2B), sometimes a partial agonist (e.g. D2L), and sometimes a full agonist (D3, D4). Aripiprazole was frequently found to be a partial agonist, with an intrinsic activity that could be low (D2L, 5-HT2A, 5-HT7), intermediate (5-HT1A), or high (D4, 5-HT2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has ‘functionally selective’ actions. The ‘functional-selectivity’ hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially ‘sensed’ by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D2-dopamine receptors are clearly cell-type specific (e.g. agonism, antagonism, partial agonism), and are most parsimoniously explained by the ‘functional selectivity’ hypothesis.
Since 5-HT2C receptors have been implicated in the control of depression, OCD, and appetite, agonism at the 5-HT2C receptor might be associated with therapeutic potential in obsessive compulsive disorder, obesity, and depression. 5-HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of 5-HT2C receptors; it is conceivable that the 5-HT2C agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an anti-obsessional agent, it is worthwhile noting that a variety of 5-HT2A/5-HT2C agonists have shown promise as anti-obsessional agents, yet many of these compounds are hallucinogenic, presumably due to 5-HT2A activation. Aripiprazole has a favourable pharmacological profile in being a 5-HT2A antagonist and a 5-HT2C partial agonist. Based on this profile, one can predict that aripiprazole may have anti-obsessional and anorectic actions in humans.
Wood and Reavill’s (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D2 receptor without significantly affecting the majority of serotonin receptors. A positron emission tomography imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D2 receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT2A receptor and only 16% occupancy of the 5-HT1A receptor. It has been suggested that the low occupancy of the 5-HT1A receptor by aripiprazole may have been an erroneous measurement however.
Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms. Due to its agonist activity on D2 receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduce.
Pharmacokinetics
Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3-5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via faeces and urine.
Chemistry
Aripiprazole is a phenylpiperazine and is chemically related to nefazodone, etoperidone, and trazodone. It is unusual in having twelve known crystalline polymorphs.
Society and Culture
Classification
Aripiprazole has been described as the prototypical third-generation antipsychotic, as opposed to first-generation (typical) antipsychotics like haloperidol and second-generation (atypical) antipsychotics like clozapine. It has received this classification due to its partial agonism of dopamine receptors, and is the first of its kind in this regard among antipsychotics, which before aripiprazole acted only as dopamine receptor antagonists. The introduction of aripiprazole has led to a paradigm shift from a dopamine antagonist-based approach to a dopamine agonist-based approach for antipsychotic drug development.
Research
Attention Deficit Hyperactivity Disorder
Aripiprazole was under development for the treatment of attention-deficit hyperactivity disorder (ADHD), but development for this indication was discontinued. A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD. A 2013 systematic review of aripiprazole for ADHD similarly reported that there is insufficient evidence of effectiveness to support aripiprazole as a treatment for the condition. Although all 6 non-controlled open-label studies in the review reported effectiveness, two small randomised controlled trials found that aripiprazole did not significantly decrease ADHD symptoms. A high rate of adverse effects with aripiprazole such as weight gain, sedation, and headache was noted. Most research on aripiprazole for ADHD is in children and adolescents. Evidence on aripiprazole specifically for adult ADHD appears to be limited to a single case report.
Substance Dependence
Aripiprazole has been studied for the treatment of amphetamine dependence and other substance use disorders, but more research is needed to support aripiprazole for these potential uses. Available evidence of aripiprazole for amphetamine dependence is mixed. Some studies have reported attenuation of the effects of amphetamines by aripiprazole, whereas other studies have reported both enhancement of the effects of amphetamines and increased use of amphetamines by aripiprazole. As such, aripiprazole may not only be ineffective but potentially harmful for treatment of amphetamine dependence, and caution is warranted with regard to its use for such purposes.
Other Uses
Aripiprazole is under development for the treatment of agitation and pervasive child development disorders. As of May 2021, it is in phase 3 clinical trials for these indications.
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Disruptive mood dysregulation disorder (DMDD) is a mental disorder in children and adolescents characterised by a persistently irritable or angry mood and frequent temper outbursts that are disproportionate to the situation and significantly more severe than the typical reaction of same-aged peers.
DMDD was added to the DSM-5 as a type of depressive disorder diagnosis for youths. The symptoms of DMDD resemble those of attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), anxiety disorders, and childhood bipolar disorder.
DMDD first appeared as a disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) in 2013 and is classified as a mood disorder. Treatments include medication to manage mood symptoms as well as individual and family therapy to address emotion-regulation skills. Children with DMDD are at risk for developing depression and anxiety later in life.
Brief History
Beginning in the 1990s, some clinicians began observing children with hyperactivity, irritability, and severe temper outbursts. These symptoms greatly interfered with their lives at home, school, and with friends. Because other diagnoses, like ADHD and ODD, did not capture the severity of children’s irritability and anger, many of these children were diagnosed with bipolar disorder. Longitudinal studies showed that children with chronic irritability and temper outbursts often developed later problems with anxiety and depression, and rarely developed bipolar disorder in adolescence or adulthood. Consequently, the developers of DSM-5 created a new diagnostic label, DMDD, to describe children with persistent irritability and angry outbursts. In 2013, the American Psychiatric Association (APA) added DMDD to the DSM-5 and classified it as a depressive disorder.
Signs and Symptoms
Children with DMDD show severe and recurrent temper outbursts three or more times per week. These outbursts can be verbal or behavioural. Verbal outbursts often are described by observers as “rages”, “fits”, or “tantrums”. Children may scream, yell, and cry for excessively long periods of time, sometimes with little provocation. Physical outbursts may be directed toward people or property. Children may throw objects; hit, slap, or bite others; destroy toys or furniture; or otherwise act in a harmful or destructive manner.
Children with DMDD also display persistently irritable or angry mood that is observable by others. Parents, teachers, and classmates describe these children as habitually angry, touchy, grouchy, or easily “set off”. Unlike the irritability that can be a symptom of other childhood disorders, such as ODD, anxiety disorders, and major depressive disorder (MDD), the irritability displayed by children with DMDD is not episodic or situation-dependent. In DMDD, the irritability or anger is severe and is shown most of the day, nearly every day in multiple settings, lasting for one or more years.
The DSM-5 includes several additional diagnostic criteria which describe the duration, setting, and onset of the disorder: the outbursts must be present for at least 12 months and occur in at least two settings (e.g. home and school), and it must be severe in at least one setting. Symptoms appear before the age of 10, and diagnosis must be made between ages 6 and 18.
Comorbidity
The core features of DMDD – temper outbursts and chronic irritability – are sometimes seen in children and adolescents with other psychiatric conditions. Differentiating DMDD from these other conditions can be difficult. Three disorders that most closely resemble DMDD are ADHD, oppositional defiant disorder (ODD), and bipolar disorder in children.
ADHD
ADHD is a neurodevelopmental disorder characterised by problems with inattention and/or hyperactivity-impulsivity.
ODD
ODD is a disruptive behaviour disorder characterised by oppositional, defiant, and sometimes hostile actions directed towards others.
Bipolar Disorder
One of the main differences between DMDD and bipolar disorder is that the irritability and anger outbursts associated with DMDD are not episodic; symptoms of DMDD are chronic and displayed constantly on an almost daily basis. On the other hand, bipolar disorder is characterised by distinct manic or hypomanic episodes usually lasting a few days, or a few weeks at most, that parents should be able to differentiate from their child’s typical mood and behaviour in between episodes. The DSM precludes a dual diagnosis of DMDD and bipolar disorder. Bipolar disorder alone should be used for youths who show classic symptoms of episodic mania or hypomania.
Prior to adolescence, DMDD is much more common than bipolar disorder. Most children with DMDD see a decrease in symptoms as they enter adulthood, whereas individuals with bipolar disorder typically display symptoms for the first time as teenagers and young adults. Children with DMDD are more at risk for developing MDD or generalised anxiety disorder when they are older rather than bipolar disorder.
Causes
Youth with DMDD have difficulty attending, processing, and responding to negative emotional stimuli and social experiences in their everyday lives. For example, some studies have shown youths with DMDD to have problems interpreting the social cues and emotional expressions of others. These youths may be especially bad at judging others’ negative emotional displays, such as feelings of sadness, fearfulness, and anger. Functional MRI studies suggest that under-activity of the amygdala, the brain area that plays a role in the interpretation and expression of emotions and novel stimuli, is associated with these deficits. Deficits in interpreting social cues may predispose children to instances of anger and aggression in social settings with little provocation. For examples, youths with DMDD may selectively attend to negative social cues (e.g. others scowling, teasing) and minimize all other information about the social events. They may also misinterpret the emotional displays of others, believing others’ benign actions to be hostile or threatening. Consequently, they may be more likely than their peers to act in impulsive and angry ways.
Children with DMDD may also have difficulty regulating negative emotions once they are elicited. To study these problems with emotion regulation, researchers asked children with DMDD to play computer games that are rigged so that children will lose. While playing these games, children with DMDD report more agitation and negative emotional arousal than their typically-developing peers. Furthermore, youths with DMDD showed markedly greater activity in the medial frontal gyrus and anterior cingulate cortex compared to other youths. These brain regions are important because they are involved in evaluating and processing negative emotions, monitoring one’s own emotional state, and selecting an effective response when upset, angry, or frustrated. Altogether, these findings suggest that youths with DMDD are more strongly influenced by negative events than other youths. They may become more upset and select less effective and socially acceptable ways to deal with negative emotions when they arise.
Treatment
Medication
Evidence for treatment is weak, and treatment is determined based on the physician’s response to the symptoms that people with DMDD present. Because the mood stabilizing medication, lithium, is effective in treating adults with bipolar disorder, some physicians have used it to treat DMDD although it has not been shown to be better than placebo in alleviating the signs and symptoms of DMDD.[7] DMDD is treated with a combination of medications that target the child’s symptom presentation. For youths with DMDD alone, antidepressant medication is sometimes used to treat underlying problems with irritability or sadness. For youths with unusually strong temper outbursts, an atypical antipsychotic medication, such as risperidone, may be warranted. Both medications, however, are associated with significant side effects in children. Finally, for children with both DMDD and ADHD, stimulant medication is sometimes used to reduce symptoms of impulsivity.
Psychosocial
Several cognitive-behavioural interventions have been developed to help youths with chronic irritability and temper outbursts. Because many youths with DMDD show problems with ADHD and oppositional-defiant behaviour, experts initially tried to treat these children using contingency management. This type of intervention involves teaching parents to reinforce children’s appropriate behaviour and extinguish (usually through systematic ignoring or time out) inappropriate behaviour. Although contingency management can be helpful for ADHD and ODD symptoms, it does not seem to reduce the most salient features of DMDD, namely, irritability and anger.
Epidemiology
There are not good estimates of the prevalence of DMDD, but primary studies have found a rate of 0.8 to 3.3%. Epidemiological studies show that approximately 3.2% of children in the community have chronic problems with irritability and temper, the essential features of DMDD. These problems are probably more common among clinic-referred youths. Parents report that approximately 30% of children hospitalised for psychiatric problems meet diagnostic criteria for DMDD; 15% meet criteria based on the observations of hospital staff.
This page is based on the copyrighted Wikipedia article <https://en.wikipedia.org/wiki/Disruptive_mood_dysregulation_disorder >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
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