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Carbatrol

Carbatrol

Carbamazepine (Biston^®; Calepsin^®; Carbatrol^®; Epitol^®; Finlepsin^®; Sirtal^®; Stazepine^®; Tegretol^®; Telesmin^®; Timonil^®) is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy and bipolar disorder; but also used to treat schizophrenia and trigeminal neuralgia.

Mechanisms

The mechanism of action of carbamazepine and its derivatives is not well understood, but appears to be primarily through the inhibition of sodium channel activity.

Side Effects

Carbamazepine renders birth control pills ineffective. Common side effects include: drowsiness, loss of blood cells, loss of platelets, motor-coordination impairment, and/or upset stomach. Very rare side effects: loss of blood cells, loss of platelets. These side effects can be life-threatening if unnoticed so frequent simple blood tests are required for the first few months followed by three or four a year to detect them. Use of carbamazepine can result in blurry or doubled vision. For people with bothersome side effects such as nausea, Tegretol XR® or Carbatrol® taken every 12 hours can greatly increase tolerability. There are reports of a bizarre auditory side effect, whereby patients perceive musical notes about a semitone lower than they truly are. (Middle C would be heard as a B.) Oxcarbazepine is a derivative of carbamazepine which has fewer and less serious side effects.

History

Carbamazepine was discovered at Geigy in Basel in 1953 by a chemist named Walter Schindler, who also synthesized the drug in 1960. The drug's anti-epileptic properties were discovered later. Carbamazepine was first marketed as a drug to treat trigeminal neuralgia in 1962.

Reference

- Schindler W, Häfliger F. Über derivate des iminodibenzyls. Helv Chim Acta 1954;37:472-483.

External links

- [http://www.rxlist.com/cgi/generic/carbam.htm TA warning]
- [http://www.psycheducation.org/depression/meds/carbamazepine.htm Carbamazepine overview] from PsychEducation.org
- [http://patimg1.uspto.gov/.piw?Docid=02948718&homeurl=http%3A%2F%2Fpatft.uspto.gov%2Fnetacgi%2Fnph-Parser%3FSect1%3DPTO1%2526Sect2%3DHITOFF%2526d%3DPALL%2526p%3D1%2526u%3D%2Fnetahtml%2Fsrchnum.htm%2526r%3D1%2526f%3DG%2526l%3D50%2526s1%3D2,948,718.WKU.%2526OS%3DPN%2F2,948,718%2526RS%3DPN%2F2,948,718&PageNum=&Rtype=&SectionNum=&idkey=2A0649DBED16 U.S. Patent 2,948,718 of August 1960] Category:Carboxamides Category:Anticonvulsants Category:Mood stabilizers

Anticonvulsant

The anticonvulsants, sometimes also called antiepileptics, belong to a diverse group of pharmaceuticals used in prevention of the occurrence of epileptic seizures. Many typical anticonvulsants work by blocking voltage-sensitive sodium channels in the brain.

Aldehydes

Main article: Aldehydes
- Paraldehyde

Aromatic Allylic Alcohols

- Stiripentol

Barbiturates

Main article: Barbiturates Barbiturates are drugs that acts as central nervous system (CNS) depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. Some also are used as anticonvulsants. The following are barbiturates:
- Methylphenobarbital
- Phenobarbital :
- Phenobarbitone :
- Phenobarbitone sodium
- Barbexaclone
- Metharbital

Benzodiazepines

Main article: Benzodiazepines The benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsive, amnestic and muscle relaxant properties. They are believed to act on the GABA_A receptor, the activation of which dampens higher neuronal activity. They began to be widely prescribed for stress-related ailments in the 1960s and 1970s. Benzodiazepines are often used for short-term relief of severe, disabling anxiety. Long-term use can be problematic due to the development of tolerance and dependency. These drugs are preferred to the use of barbiturates because they have a lower abuse potential and relatively lower adverse reactions and interactions. However, drowsiness, ataxia, confusion, vertigo, impaired judgement, and a number of other effects are still common. The following are benzodiazepines. These drugs are listed in order of the shortest acting to the longest acting (by the approximate half-life of the drug), however this time may greatly vary between persons.
- Triazolam ("Halcion") - 2 hours
- Midazolam ("Versed") - 3 hours [1.8-6 hours]
- Oxazepam ("Serax") - 4-15 hours
- Chlordiazepoxide ("Librium") - 5-25 hours
- Alprazolam ("Xanax") - 6-12 hours
- Temazepam ("Restoril") 8-20 hours
- Lorazepam ("Ativan") 10-20 hours
- Bromazepam ("Lexotan") 10-20 hours
- Estazolam ("ProSom") 10-24 hours
- Clobazam ("Frisium") 18 hours
- Flunitrazepam ("Rohypnol") 18-26 hours. Considered a "date-rape drug"
- Clonazepam ("Klonopin", "Rivotril") 18-50 hours
- Quazepam ("Doral") 25-100 hours
- Clorazepate ("Tranxene") 36-100 hours
- Medazepam ("Nobrium") 36-150 hours
- Prazepam ("Centrax") 36-200 hours
- Diazepam ("Valium") 36-200 hours
- Flurazepam ("Dalmane") 40-250 hours

Bromides

Main article: Bromides
- Potassium bromide

Carbamates

Main article: Carbamates
- Felbamate
- Meprobamate ("Miltown")
- Emylcamate
- Phenprobamate

Carboxamides

Main article: Carboxamides The following are carboxamides:
- Carbamazepine
- Oxcarbazepine

Fatty Acids

Main article: Fatty acids The following are fatty-acids:
- The valproates — valproic acid, sodium valproate, and divalproex sodium
- Vigabatrin
- Progabide
- Tiagabine Vigabatrin and progabide are also analogs of GABA.

Fructose Derivatives

Main article: Fructose
- Topiramate

GABA Analogs

- Gabapentin
- Pregabalin

Hydantoins

Main article: Hydantoins As hydantoins have a slow onset of action, they are not recommended for acute control of epilepsy. The following are hydantoins:
- Ethotoin
- Phenytoin
- Mephenytoin
- Fosphenytoin

Oxazolidinediones

Main article: Oxazolidinediones The following are oxazolidinediones:
- Paramethadione
- Trimethadione
- Ethadione

Propionates

Main article: Propionates
- Beclamide

Pyrimidinediones

Main article: Pyrimidinediones
- Primidone

Pyrrolidines

Main article: Pyrrolidines
- Brivaracetam
- Levetiracetam
- Seletracetam

Succinimides

Main article: Succinimides The following are succinimides:
- Ethosuximide
- Phensuximide
- Mesuximide

Sulfonamides

Main article: Sulfonamides
- Acetazolamide
- Sultiame
- Methazolamide
- Zonisamide

Triazines

Main article: Triazines
- Lamotrigine

Ureas

Main article: Ureas
- Pheneturide
- Phenacemide

Valproylamides (Amide Derivatives of Valproate)

Main article: Amides
- Valpromide
- Valnoctamide

References and end notes

# [http://www.biam2.org/www/Sub5044.html FELBAMATE] Biam # [http://www.biam2.org/www/Sub2341.html MEPROBAMATE] Biam # [http://www.biam2.org/www/Sub2770.html EMYLCAMATE] Biam # Green, Ben [http://www.priory.com/focus7.htm Focus on Topiramate - a new anti-epileptic] Priory Lodge Education Ltd., 1997-99. Focus on Topiramate First published May 1997. Version 1.1 # Neyens LG, Alpherts WC, Aldenkamp AP. "Cognitive effects of a new pyrrolidine derivative (levetiracetam) in patients with epilepsy." Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1995 May;19(3):411-9. PMID 7624492 [http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TBR-3YB9TDB-27-1&_cdi=5149&_user=10&_orig=search&_coverDate=05%2F31%2F1995&_qd=1&_sk=999809996&view=c&wchp=dGLbVtb-zSkWW&md5=6616cf9dc0f863fc00f3696d117007a8&ie=/sdarticle.pdf Elsevier Fulltext]
- th:แอนติอิพิเลปติก

Mood stabilizer

A mood stabilizer is a psychiatric medication used in the treatment mood disorders characterised by rapid and unstable mood shifts. These disorders include bipolar disorder, where they suppress swings between mania and depression, and Borderline Personality Disorder. Most mood stabilizers are anticonvulsants, with the important exception of lithium. Mood stabilizers include:
- Lithium carbonate - The first FDA approved mood stabilizer, and still often the primary one used. Therapeutic drug monitoring required. Monitor blood lithium levels (therapeutic range: 0.6 or 0.8 - 1.2 mEq/L) and look for signs and symptoms of toxicity (such as nausea, vomiting, diarrhea, ataxia).
- Valproic acid, divalproex sodium (Depakote^®), and sodium valproate (Depacon^®) - Available in extended release form. Can be very irritating to the stomach, especially when taken as valproic acid. Liver function and CBC should be monitored. Therapeutic drug monitoring is required.
- Lamotrigine (Lamictal^®) - Particularly effective for bipolar depression. Monitor for signs and symptoms of Stevens-Johnson syndrome, very rare but can be fatal.
- Carbamazepine (Tegretol^®) - CBC should be monitored; can lower white blood cell count. Therapeutic drug monitoring is required. Not FDA approved for bipolar disorder, but widely used for many years.
- Gabapentin (Neurontin^®) Not FDA approved for bipolar disorder. Recent scientific studies suggest it is not an effective treatment, however many psychiatrists continue to use.
- Oxcarbazepine (Trileptal^®) Not FDA approved for bipolar disorder.
- Topiramate (Topamax^®) Not FDA approved for bipolar disorder. Sometimes mood stabilizers are used in combination, such as lithium with one of the anticonvulsants. Many antipsychotics also have mood stabilizing effects and are thus commonly prescribed even when psychotic symptoms are absent. It is also conjectured that Omega-3 fatty acids may have a mood stabilizing effect. However, more research is needed to verify this (a multi-year study of this is now being carried out as of 2001). Most mood stabilizers are effective at treating mania and mood cycling and shifting, but are not very effective at treating depression (with lamotrigine an exception). Often, an antidepressant is prescribed in addition to the mood stabilizer during depressive phases. However this brings some risks, as antidepressants can induce mania, psychosis, and other disturbing problems in bipolar patients, particularly when taken alone, but sometimes even when used with a mood stabilizer.

References

- Manic-Depressive Illness by Frederick K. Goodwin and Kay Redfield Jamison.

External link

[http://www.mcmanweb.com/article-23.htm Bipolar Medications - The Mood Stabilizers] Category:Psychoactive drugs
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Epilepsy

Epilepsy (often referred to as a seizure disorder) is a chronic neurological condition characterized by recurrent unprovoked seizures. The condition is named from the Greek epilepsia ("a taking hold of or seizing"). It is commonly controlled with medication, although surgical methods are used as well.

Causes

All the causes (or etiologies) of epilepsy are not known, but many predisposing factors have been identified, including brain damage resulting from malformations of brain development, head trauma, neurosurgical operations, other penetrating wounds of the brain, brain tumor, high fever, bacterial or viral encephalitis, stroke, intoxication, or acute or inborn disturbances of metabolism. Hereditary or genetic factors also play a role. Epileptic seizures may occur in any person under certain circumstances, including acute illness and drug overdoses, but these provoked seizures are not part of the definition of epilepsy. Epilepsy connotes that an individual has unprovoked seizures which recur over time. In about 50% of all cases, there is no cause for epilepsy that is currently detectable even with state of the art investigations. In about 50% of cases, evidence of a brain injury, scar or malformation is found, to which the epilepsy is attributed. In many, but not all cases, abnormal electrical activity can be detected in the brain with an electroencephalogram (EEG), either during or in between seizures. Some people (especially young children) have seizures when exposed to certain patterns of flashing/flickering lights. This is a special type of reflex epilepsy called photosensitive epilepsy and the seizures themselves are often informally called "Pokemon seizures," after an article was published describing an outbreak of photosensitive seizures due to broadcast of an episode of the popular children's television show Pokemon. While some of the children involved doubtless had photosensitive epilepsy, some investigators believe that the majority of the 12,000 affected in this outbreak actually were having psychogenic non-epileptic seizures. The most common ages of incidence are under the age of 18 and over the age of 65. It has been estimated that about 1% of the population meets the diagnostic criteria for epilepsy at any given time, but some theorize that the prevalence may be much higher in fact. A significant and measurable decline in cognitive function is known to be associated with epilepsy, although it has not been entirely clear to what extent this is due to the epilepsy itself or to the drugs used to treat it. Phenobarbital, in particular, has been shown to decrease IQ and classroom performance when used to treat epilepsy in children; the effects persist after the phenobarbital is stopped. Some newer anti-epileptic drugs are considered by some to have less severe cognitive effects than older drugs. On an individual level, a person's reaction to epileptic seizures and/or anti-epileptic drugs may be idiosyncratic, so it is difficult to predict how a particular person might be affected. Mutations in several genes have been linked to some types of epilepsy. Several genes that code for protein subunits of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes. Several ligand-gated ion channels have been linked to some types of frontal and generalized epilepsies. Epilepsy-related mutations in some non-ion channel genes have also been identified. One interesting finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold." This phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire) was discovered by Dr. Graham Goddard in 1967. Chemical stimulation can also induce seizures; repeated exposures to some pesticides have been shown to induce seizures in both humans and animals. One mechanism proposed for this is called excitotoxicity. The roles of kindling and excitotoxicity, if any, in human epilepsy are currently hotly debated.

Diagnosis

The diagnosis of epilepsy requires the presence of recurrent, unprovoked seizures; accordingly, it is usually made based on the medical history. EEG, brain MRI, SPECT, PET, and magnetoencephalography may be useful to discover an etiology for the epilepsy, discover the affected brain region, or classify the epileptic syndrome, but these studies are not useful in making the initial diagnosis. Long-term video-EEG monitoring for epilepsy is the gold standard for diagnosis, but it is not routinely employed owing to its high cost and inconvenience. It is, however, sometimes used to distinguish psychogenic non-epileptic seizures from epilepsy. Convulsive or other seizure-like activity, non-epileptic in origin, can be observed in many other medical conditions, including:
- psychogenic non-epileptic seizures (often wrongly called "pseudoseizures")
- tics
- syncope (fainting)
- narcolepsy
- cataplexy
- parasomnias
- breath-holding spells of childhood
- non-epileptic myoclonus
- hypoglycemia and associated neuroglycopenia
- opsoclonus
- hyperekplexia
- paroxysmal kinesiogenic dyskinesia
- infantile gratification / masturbation (onanism)
- repetitive behaviors Neurologists are often called upon to distinguish among the above diagnoses and epilepsy.

Types of seizure

Epileptic seizures are classified both by their patterns of activity in the brain and their effects on behaviour. In terms of their pattern of activity, seizures may be described as either partial (focal) or generalised. Partial seizures only involve a localised part of the brain, whereas generalised seizures involve the entire cortex. The term 'secondary generalisation' may be used to describe a partial seizure that later spreads to the whole of the cortex and becomes generalised. Partial seizures may be further subdivided into both simple and complex seizures. This refers to the effect of such a seizure on consciousness; simple seizures cause no interruption to consciousness (although they may cause sensory distortions or other sensations), whereas complex seizures interrupt consciousness to varying degrees. This does not necessarily mean that the person experiencing this sort of seizure will fall unconscious (like fainting). For example, a complex partial seizure may involve the unconscious repetition of simple actions, gestures or verbal utterances, or simply a blank stare and apparent unawareness of the occurrence of the seizure, followed by no memory of the seizure. Other patients may report a feeling of tunnel vision or dissociation, which represents a diminishment of awareness without full loss of consciousness. Still other patients can perform complicated actions, such as travel or shopping, while in the midst of a complex partial seizure. The effects of partial seizures can be quite dependent on the area of the brain in which they are active. For example, a partial seizure in areas involved in perception may cause a particular sensory experience (for example, the perception of a scent, music or flashes of light) whereas, when centred in the motor cortex, a partial seizure might cause movement in particular groups of muscles. This type of seizure may also produce particular thoughts or internal visual images or even experiences which may be distinct but not easily described. Seizures centred on the temporal lobes are known to produce mystical or ecstatic experiences in some people. These may result in a misdiagnosis of psychosis or even schizophrenia, if other symptoms of seizure are disregarded and other tests are not performed. Unfortunately for those with epilepsy, anti-psychotic medications prescribed without anti-convulsants in this case can actually lower the seizure threshold further and worsen the symptoms. When the effects of a partial seizure appear as a 'warning sign' before a more serious seizure, they are known as an aura: it is frequently the case that a partial seizure will spread to other parts of the brain and eventually become generalized, resulting in a tonic-clonic convulsion. The subjective experience of an aura, like other partial seizures, will tend to reflect the function of the affected part of the brain. Generalised seizures can be sub-classified into a number of categories, depending on their behavioural effects:
- Absence seizures (sometimes referred to as petit mal seizures) involve an interruption to consciousness where the person experiencing the seizure seems to become vacant and unresponsive for a short period of time (usually up to 30 seconds). Slight muscle twitching may occur.
- Tonic-clonic seizures (sometimes referred to as grand mal seizures), involve an initial contraction of the muscles (tonic phase) which may involve tongue biting, urinary incontinence and the absence of breathing. This is followed by rhythmic muscle contractions (clonic phase). This type of seizure is usually what is referred to when the term 'epileptic fit' is used colloquially.
- Myoclonic seizures involve sporadic muscle contraction and can result in jerky movements of muscles or muscle groups.
- Atonic seizures involve the loss of muscle tone, causing the person to fall to the ground. These are sometimes called 'drop attacks' but should be distinguished from similar looking attacks that may occur in narcolepsy or cataplexy.
- Status epilepticus refers to continuous seizure activity with no recovery between successive tonic-clonic seizures. This is a life-threatening condition and emergency medical assistance should be called immediately if this is suspected. A tonic-clonic seizure lasting longer than 5 minutes (or two minutes longer than a given person's usual seizures) is usually considered grounds for calling the emergency services.
- Epilepsia partialis continua is a rare type of focal motor seizure (hands and face) which recurs every few seconds or minutes for extended periods (days or years). It is usually due to strokes in adults and focal cortical inflammatory processes in children (Rasmussen's encephalitis), possibly caused by chronic viral infections or autoimmune processes.

Seizure Syndromes

It is important to note that seizures are symptoms of specific illnesses, one example being epilepsy. Other diseases that can cause seizures include brain tumors, infection (e.g., encephalitis), traumatic injury to the brain, and metabolic or electrolyte abnormalities. Seizures arising from these conditions are not considered epilepsy because, once the inciting event is removed or alleviated, the seizures stop. There are many different epilepsy syndromes, each presenting with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis. Below are some common seizure syndromes:
- Infantile spasms (West syndrome) is associated with brain development abnormalities, tuberous sclerosis, and perinatal insults to the brain. It affects infants (as implied by its name), which by definition is between 30 days to 1 year of life. It carries a poor prognosis such that only 5-10% of children with infantile spasms will develop normal to near-normal function, while more than two-thirds will have severe deficits. The typical seizures are characterized by sudden flexor and extensor spasms of head, trunk, and extremities. The key EEG finding in these patients is a hypsarrythmia, or a high-voltage slow wave with multifocal spikes. The first line treatment for these patients is adrenocorticotropic hormone ([ACTH]] or [[corticotropin) since traditional antiepileptic drugs generally cannot adequately control seizure activity. Vigabatrin is also used in many countries, and is particularly effective when tuberous sclerosis is the cause of seizures.
- Childhood absence epilepsy affects children between the ages of 4 and 12 years of age. These patients have recurrent absence seizures that can occur hundreds of times a day. On EEG, one finds the stereotyped generalized 3 Hz spike and wave discharges. A subset of these patients will also develop generalized tonic-clonic seizures. This condition carries a fairly good prognosis in that these children do not usually show cognitive decline or neurological deficits. First line treatment for pure absence seizures is ethosuximide. If patients do not respond or have mixed seizures along with their absence seizures, then valproic acid can be used.
- Benign focal epilepsy of childhood (Benign Rolandic epilepsy) begins in children between the ages of 4 and 13 years. Apart from their seizure disorder, these patients are otherwise normal. Seizures occur at night and sleep promotes secondary generalization. As such, parents only report generalized seizures because focal manifestations are often subtle and go unnoticed. Between seizures, patients have a stereotyped EEG pattern that includes di- or triphasic sharp waves over the central-midtemporal (Rolandic) regions. Progosnis is uniformly good with seizures disappearing by adolescence. Carbamazepine is the first line treatment, though phenytoin and phenobarbital have also been used with some efficacy.
- Juvenile myoclonic epilepsy (JME) begins in patients aged 8 to 20 years. These patients have normal IQ and are otherwise neurologically intact. There is usually a family history of similar seizures. The seizures are morning myoclonic jerks often with generalized tonic-clonic seizures that occur just after waking. EEG readings reveal generalized spikes with 4-6 Hz spike wave discharges and multiple spike discharges. Interestingly, thse patients are often first diagnosed when they have their first generalized tonic-clonic seizure later in life when they experience sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Valproic acid is the first line treatment. This condition is lifelong, thus patients must be taught appropriate sleep hygiene to prevent generalized tonic-clonic seizures.
- Temporal lobe epilepsy is the most common epilepsy of adults. In most cases, the epileptogenic region is found in the mesial temporal structures (e.g., the hippocampus, amygdala, and parahippocampal gyrus). Seizures begin in late childhood and adolescence. There is an association with febrile seizures in childhood, and some studies have shown herpes simplex virus (HSV) DNA in these regions, suggesting that perhaps this epilepsy has an infectious etiology. Most of these patients have complex partial seizures often preceded by an aura.
- Frontal lobe epilepsy
- Lennox-Gastaut syndrome

Treatment

Epilepsy is usually treated with medication prescribed by a physician; primary caregivers, neurologists, and neurosurgeons all frequently care for people with epilepsy. In some cases the implantation of a stimulator of the vagus nerve, or a special diet can be helpful. Neurosurgical operations for epilepsy can be palliative, reducing the frequency or severity of seizures; or, in some patients, an operation can be curative.

Responding to a seizure

In most cases, the proper emergency response to a generalized tonic-clonic epileptic seizure is simply to prevent the patient from self-injury by moving him or her away from sharp edges, placing something soft beneath the head, and carefully rolling the person onto his or her side to avoid asphyxiation. Should the person regurgitate, the material should be allowed to drip out the side of the patient's mouth by itself. If the seizure lasts longer than 5 minutes, Emergency Medical Services should be contacted. Prolonged seizures may develop into status epilepticus, a dangerous condition requiring hospitalization and emergency treatment. Objects should never be placed in a person's mouth during a seizure as this could result in injury to the person's mouth or obstruction of the airway. Despite common folklore, it is not possible for a person to swallow their own tongue during a seizure. After a seizure, it is typical for a person to be confused, disoriented, and possibly agitated or sleepy. It is important to stay with the person until this passes; people should not eat or drink until they have returned to their normal level of awareness, and they should not be allowed to wander about unsupervised. Many patients will sleep deeply for a few hours after a seizure; this is not dangerous. In about 50% of people with epilepsy, headaches may occur after a seizure. These headaches share many features with migraines, and respond to the same medications.

Pharmacologic treatment

Some medications can be taken daily in order to prevent seizures altogether or reduce the frequency of their occurence. These are termed "anticonvulsant" or "antiepileptic" drugs (sometimes AEDs). All such drugs have side effects which are idiosyncratic and others which are dose-dependent; it is not possible to predict who will suffer from side effects or at what dose the side effects will appear. Some people with epilepsy will experience a complete remission when treated with an anticonvulsant medication. If this does not occur, the dose of medication may be increased, or another medication may be added to the first. The general strategy is to increase the medication dose until either the seizures are controlled, or until dose-limiting side effects appear; at which point the medication dose is reduced to the highest amount that did not produce undesirable side effects. Serum levels of AEDs can be checked to determine medication compliance and to assess the effects of drug-drug interactions; serum levels are generally not useful to predict anticonvulsant efficacy in an individual patient, though in some cases (such as a seizure flurry) it can be useful to know if the level is very high or very low. If a person's epilepsy cannot be brought under control after adequate trials of two different drugs, that person's epilepsy is generally said to be 'medically refractory.' Various drugs may prevent seizures or reduce seizure frequency: these include carbamazepine (brand name Tegretol), clobezam (Frisium), clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), flurazepam (Dalmane), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), mephenytoin (Mesantoin), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone (Mysoline), tiagabine (Gabitril), topiramate (Topamax), valproate, sodium divalproex (Depakene, Depakote), and vigabatrin (Sabril). Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry; these include diazepam (Valium) and lorazepam (Ativan). Drugs used only in the treatment of refractory status epilepticus include paraldehyde (Paral) and pentobarbital (Nembutal). Bromides were the first of the effective anticonvulsant pure compounds, but are no longer used due to their toxicities and low efficacy.

Surgical Treatment

Surgical treatment can be an option for epilepsy when an underlying brain abnormality, such as a benign tumor or an area of scar tissue (e.g. hippocampal sclerosis) can be identified. The abnormality must be removable by a neurosurgeon. Surgery is usually only offered to patients when their epilepsy has not been controlled by adequate attempts with multiple medications. Before surgery is offered, the medical team performs many tests to assess whether removal of brain tissue will result in unacceptable problems with memory, vision, language or movement, which are controlled by different parts of the brain. Resective surgery, as opposed to palliative, successfully eliminates or significantly reduces seizures in about 80% of the patients who undergo it. Many patients decide not to undergo surgery owing to fear or the uncertainty of having a brain operation. The most common form of resective surgical treatment for epilepsy is to remove a portion of either the right or left temporal lobe, depending on where the seizures are occurring. A study of 48 patients who underwent this operation, anterior temporal lobectomy, between 1965 and 1974 determined the long-term success of the procedure. Of the 48 patients, 21 had had no seizures that caused loss of conciousness since the operation. Three others had been free of seizures for at least 19 years. The rest had either never been completely free of seizures or had died between the time of the surgery and commencement of the study. (Kelley & Theodore, 2005) Palliative surgery for epilepsy is designed to reduce the frequency or severity of seizures. Examples are callosotomy or commissurotomy, which can prevent seizures from generalizing (spreading to involve the entire brain). Since people whose seizures generalize often lose consciousness and fall over backwards, injuring themselves, this can be quite valuable, especially when the seizures cannot be controlled by other means. Resective surgery is on occasion undertaken with the expectation that it will reduce but not eliminate seizures; this would be considered palliative surgery. Hemispherectomy is a drastic operation in which most or all of one half of the cerebral cortex is removed. It is reserved for the most catastrophic epilepsies, such as those due to Rasmussen syndrome. If the surgery is performed on very young patients (2-5 years old), the remaining hemisphere may acquire some rudimentary motor control of the ipsilateral body; in older patients, paralysis results on the side of the body opposite to the part of the brain that was removed. Because of these and other side effects it is usually reserved for patients who have exhausted other treatment options.

Other Treatment

Ketogenic diets may occasionally be effective in controlling some types of epilepsy; although the mechanism behind the effect is not fully understood, shifting of pH towards a metabolic acidosis and alteration of brain metabolism may be involved. Ketogenic diets are high in fat and extremely low in carbohydrates, with intake of fluids often limited. This treatment, originated as early as the 1920s at Johns Hopkins Medical Center, was largely abandoned with the discovery of modern anti-epileptic drugs, but recently has returned to the anti-epileptic treatment arsenal. Ketogenic diets are sometimes prescribed in severe cases where drugs have proven ineffective. There are several downsides to what initially seems a benign therapy, however. The ketogenic diet is not good for the heart or kidneys and medical problems resulting from the diet have been reported. In addition, the diet is extremely unpalatable and few patients are able to tolerate it for any length of time. Since a single potato chip is adequate to break the ketosis, staying on the diet requires either great willpower or perfect control of a person's dietary intake. People fed via gastrostomy or young children who receive all their food in the presence of a caregiver are better candidates. Vagus nerve stimulation is a recently developed form of seizure control which uses an implanted electrical device, similar in size, shape and implant location to a heart pacemaker, which connects to the vagus nerve in the neck. Once in place the device can be set to emit electronic pulses, stimulating the vagus nerve at pre-set intervals and milliamp levels. Treatment studies have shown that approximately 50% of people treated in this fashion will show significant seizure reduction. Some people with epilepsy receive a special dog which has the rare talent of sensing the onset of a seizure and is trained to alert the human so they can reach a safe location before their seizure puts them in danger. Other [http://www.keppra.com/pc/other_resources/canineAssistants.aspx epilepsy care dogs] do not sense seizures, but serve as companions and guardians during the loss of consciousness accompanying a seizure.

History and Stigma

In the past, epilepsy was associated with religious experiences and even demonic possession. Apocryphally, epilepsy has been called the "Sacred Disease" because people thought that epileptic seizures were a form of attack by demons, or that the visions experienced by persons with epilepsy were sent by the gods. However, in many cultures, persons with epilepsy have been stigmatized, shunned, or even imprisoned; in the Salpêtrière, the birthplace of modern neurology, Jean-Martin Charcot found people with epilepsy side-by-side with the mentally retarded, chronic syphilitics, and the criminally insane. In Tanzania to this day, onlookers will not touch a person having an epileptic fit, owing to fear of demons, even if the seizure causes the person to fall into the cooking fire (the flickering light from fire may have provoked the seizure in the first place.) In ancient rome epilepsy was known as the Morbus Comitialis and was seen as a curse from the gods. Stigma continues to this day, in both the public and private spheres, but polls suggest it is generally decreasing with time, at least in the developed world; Hippocrates remarked that epilepsy would be considered divine only until it was understood [http://quote.wikipedia.org/wiki/Hippocrates].

Legal implications

Most people diagnosed with epilepsy are forbidden by their local laws from operating vehicles; seizure victims have caused many fatal car accidents and plane crashes. However, there are usually special exceptions for those who can prove that they have stabilized their condition for a period of time with the help of appropriate medication. Those few whose seizures do not cause impairment of consciousness, or whose seizures only arise from sleep, may be exempt from such restrictions, depending on local laws. There is an ongoing debate in bioethics over who should bear the burden of ensuring that an epilepsy patient does not drive a car or fly an airplane. In the U.S., the majority of the 50 states place the burden on patients to report their condition to appropriate licensing authorities so that their privileges can be revoked where appropriate. A minority of states (including California) place the burden on the patient's physician. Empirical studies have demonstrated that such laws may deter epilepsy patients from seeking treatment from a physician for their condition, because they fear the loss of their driving privileges. In the UK, it is the responsibility of the patient to inform the Driver and Vehicle Licensing Agency (DVLA) if they have epilepsy. The rules are quite complex, but in summary, those continuing to have seizures or who are within 6 months of medication change may have their license revoked. A doctor who becomes aware that a patient with uncontrolled epilepsy is continuing to drive has, after reminding the patient of their responsibility, a duty to break confidentiality and inform the DVLA. The doctor should advise the patient of the disclosure and the reasons why their failure to notify the agency obliged the doctor to act.

Important investigators of epilepsy

- Galen
- Jean-Martin Charcot
- John Hughlings Jackson
- Hans Berger
- Herbert Jasper
- Wilder Penfield
- H. Houston Merritt

References

# PMID 11235034 # PMID 15955959 # PMID 16006194

External links

Worldwide non-profit organizations

- [http://www.epilepsy.org The International League Against Epilepsy (ILAE) website], supporting research and patient care worldwide.
- [http://www.epilepsyfoundation.org/ The Epilepsy Foundation], a non-profit organization with an excellent patient-oriented website.
- [http://www.epilepsy.com Epilepsy.com] - Epilepsy information for patients, families and caregivers living with epilepsy. Supported by a 501c not-for-profit affiliated with universities, drug and device manufacturers.

Regional epilepsy organizations

- [http://www.nyuepilepsy.org The NYU Comprehensive Epilepsy Center is the largest epilepsy center in the United States] - [http://www.nyuepilepsy.org nyuepilepsy.org]
- [http://www.nyufaces.org Finding A Cure for Epilepsy and Seizures (faces)] - [http://www.nyufaces.org nyufaces.org]
- [http://www.epinet.org.au The Epilepsy Foundation of Victoria] A comprehensive site for people living with epilepsy.
- [http://www.epilepsy.org.uk/info/firstaid.html What to do when someone has a seizure] - Information from Epilepsy Action
- National Institute of Neurological Disorders and Stroke [http://www.ninds.nih.gov/health_and_medical/disorders/epilepsy.htm Epilepsy Information Page] (USA)
- [http://www.epilepsyaustralia.org Epilepsy Australia] Where to go for help with epilepsy in Australia.
- [http://www.epilepsy.org.au Epilepsy Association of Australia] Information and education, seizure first aid.
- [http://www.headlines.org.au Australian Headlines, online epilepsy magazine] News, opinion, research, personal experiences
- [http://www.eqi.org.au/ Epilepsy Queensland]
- [http://epilepsy.ca/eng/mainSet.html Epilepsy Canada]
- [http://www.getontheteam.org.au Get on the Team Campaign] Epilepsy Awareness Campaign featuring high profile ambassadors. Category:Neurology ja:てんかん

Schizophrenia

:For other senses of this word, see schizophrenia (disambiguation). Schizophrenia is a severe mental illness characterized by persistent defects in the perception or expression of reality. A person experiencing untreated schizophrenia typically demonstrates grossly disorganized thinking, and may also experience delusions or auditory hallucinations. Although the illness primarily affects cognition, it can also contribute to chronic problems with behavior or emotions. Due to the many possible combinations of symptoms, it is difficult to say whether it is in fact a single psychiatric disorder; and Eugen Bleuler deliberately called the disease "the schizophrenias," (plural) when he coined the present name. Diagnosis is based on the self-reported experiences of the patient, in combination with secondary signs observed by a psychiatrist or other competent clinician such as a doctor of psychology. There is no objective biological test for schizophrenia, though studies suggest that genetics and biochemistry are important contributing factors. Current research into the development of the disorder often focuses on the role of neurobiology, although an identifiable organic cause has not been found. In the absence of objective laboratory tests to confirm the diagnosis, some question the legitimacy of schizophrenia's status as a disease. The term "schizophrenia" translates roughly as "shattered mind," and comes from the Greek σχίζω (schizo, "to split" or "to divide") and φρήν (phrēn, "mind"). Despite its etymology, schizophrenia is not synonymous with dissociative identity disorder, also known as multiple personality disorder or "split personality"; in popular culture the two are often confused. Although schizophrenia often leads to social or occupational dysfunction, there is little association of the illness with a predisposition toward aggressive behavior.

Overview

Schizophrenia is characterized by "positive symptoms" and typically also by "negative symptoms." Positive symptoms, which are regarded as manifestations of "psychosis," may include delusions, auditory hallucinations, and thought disorder. Negative symptoms may include such features as flat, blunted or constricted affect, poverty of speech, or absence of motivation. Some models of schizophrenia subsume "formal thought disorder" and planning difficulties in a third group, a "disorganization syndrome." Additionally, neurocognitive deficits may be present. These may take the form of reduced or impaired psychological functions such as memory, attention, problem-solving, executive function or social cognition. Onset of schizophrenia typically occurs in late adolescence or early adulthood, with males tending to show symptoms earlier than females. Psychiatrist Emil Kraepelin was the first to draw a distinction between what he termed dementia praecox ("premature dementia") and other psychotic illnesses. In 1911, "dementia praecox" was renamed "schizophrenia" by psychiatrist Eugen Bleuler, who found Kraepelin's term to be misleading, as the disorder is not a form of dementia, premature or otherwise. The diagnostic approach to schizophrenia has been opposed, most notably by the anti-psychiatry movement, who argue that classifying specific thoughts and behaviors as illness allows social control of people who society finds undesirable but who have committed no crime. More recently, it has been argued that schizophrenia is just one end of a spectrum of experience and behavior, and everybody in society may have some such experiences in their life. This is known as the 'continuum model of psychosis' or the 'dimensional approach' and is most notably argued for by psychologist Richard Bentall and psychiatrist Jim van Os. Although no definite causes of schizophrenia have been identified, most researchers and clinicians currently believe that schizophrenia is primarily a disorder of the brain. It is thought that schizophrenia may result from a mixture of genetic disposition (genetic studies using various techniques have shown that relatives of people with schizophrenia are more likely than the general population to show signs of schizophrenia themselves) and environmental stress (research suggests that stressful life events may precede a schizophrenic episode.) It is also thought that processes in early neurodevelopment are important, particularly prenatal processes. In adult life, particular importance has been placed upon the function (or malfunction) of dopamine in the mesolimbic pathway in the brain. This theory, known as the dopamine hypothesis of schizophrenia largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, reduced psychotic symptoms. However, this theory is now thought to be overly simplistic as a complete explanation. These drugs have now been developed further and antipsychotic medication is commonly used as a first-line treatment. Although effective in many cases, these medications are not well tolerated by many patients due to significant side-effects, and have little effect on some individuals. Differences in brain structure have been found between people with schizophrenia and those without. However, these tend only to be reliable on the group level and, due to the significant variability between individuals, may not be reliably present in any particular individual.

History

Accounts that may relate to symptoms of schizophrenia date back as far as 2000 BC in the Book of Hearts, part of the ancient Ebers papyrus. However, a recent study into the ancient Greek and Roman literature showed that, while the general population probably had an awareness of psychotic disorders, there was no recorded condition that would meet the modern diagnostic criteria for schizophrenia in these societies. This nonspecific concept of "madness" has been around for many thousands of years, but schizophrenia was only classified as a distinct mental disorder by Kraepelin in 1887. He was the first to make a distinction between schizophrenia and manic depression. The term schizophrenia is derived from the Greek words 'schizo' (split) and 'phren' (mind) and was coined by Eugene Bleuler to refer to the lack of interaction between thought processes and perception. "The patients that I have observed do not respond to situations as they should; they are frightened by what is not there, yet they remain indifferent to what is. It is as if they have a split mind." He was also the first to describe the symptoms as "positive" or "negative." Bleuler suggested the name schizophrenia, as it was obvious that Kraepelin's name was misleading. The word "praecox" implied precocious or early onset, hence premature dementia, as opposed to senile dementia from old age. Bleuler realized the illness was not a dementia, as it did not lead to mental deterioration. Rather, schizophrenia led to a sharpening of the senses and a greater awareness of memories and experiences. With the name 'schizophrenia' Bleuler intended to capture the separation of function between personality, thinking, memory, and perception, however it is commonly misunderstood to mean that affected persons have a 'split personality' (something akin to the character in Robert Louis Stevenson's The Strange Case of Dr Jekyll and Mr Hyde). Although some people diagnosed with schizophrenia may 'hear voices' and may experience the voices as distinct personalities, schizophrenia does not involve a person changing among distinct multiple personalities. The confusion perhaps arises in part due to the meaning of Bleuler's term 'schizophrenia' (literally 'split mind'). Interestingly, the first known misuse of this word schizophrenia to mean 'split personality' (in the Jekyll and Hyde sense) was in an article by the poet T. S. Eliot in 1933. In the first half of the twentieth century schizophrenia was considered by many to be a "hereditary defect", and individuals affected by schizophrenia became subject to eugenics in many countries. Hundreds of thousands were sterilized, with or without consent, the majority in Nazi Germany, the United States, and Scandinavian countries. Many people diagnosed with schizophrenia, together with other members of the "mentally unfit", were murdered in the Nazi "Operation T-4" programme.

Diagnosis

Diagnosis and presentation (signs and symptoms)

Like many mental illnesses, the diagnosis of schizophrenia is based upon the behavior of the person being assessed. There is a list of criteria that must be met for someone to be so diagnosed. These depend on both the presence and duration of certain signs and symptoms. The most commonly used criteria for diagnosing schizophrenia are from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) and the World Health Organization’s International Statistical Classification of Diseases and Related Health Problems (ICD). The most recent versions are [http://www.who.int/whosis/icd10/ ICD-10] and [http://www.psych.org/research/dor/dsm/index.cfm DSM-IV-TR]. Below is an abbreviated version of the diagnostic criteria from the DSM-IV-TR; the full version is available [http://www.behavenet.com/capsules/disorders/schiz.htm here]. (DSM cautionary statement) To be diagnosed as having schizophrenia, a person must display:
- A) Characteristic symptoms: Two or more of the following, each present for a significant portion of time during a one-month period (or less, if successfully treated)
- delusions
- hallucinations
- disorganized speech (e.g., frequent derailment or incoherence; speaking in abstracts). See thought disorder.
- grossly disorganized behavior (e.g. dressing inappropriately, crying frequently) or catatonic behavior
- negative symptoms, i.e., affective flattening (lack or decline in emotional response), alogia (lack or decline in speech), or avolition (lack or decline in motivation). :Note: Only one Criterion A symptom is required if hallucinations consist of hearing one voice participating in a running commentary of the patient's actions or of hearing two or more voices conversing with each other.
- B) Social/occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work or interpersonal relations are markedly below the level achieved prior to the onset.
- C) Duration: Continuous signs of the disturbance persist for at least six months. This six-month period must include at least one month of symptoms that meet Criterion A. Additional criteria (D, E and F) are also given that exclude a diagnosis of schizophrenia if symptoms of mood disorder or pervasive developmental disorder are present. Additionally a diagnosis of schizophrenia is excluded if the symptoms are the direct result of a substance (e.g., a drug of abuse, a medication) or a general medical condition. Historically, schizophrenia in the West was classified into catatonic, hebephrenic, and paranoid. The DSM now contains five sub-classifications of schizophrenia. These are
- catatonic type (where marked absences or peculiarities of movement are present),
- disorganized type (where thought disorder and flat affect are present together),
- paranoid type (where delusions and vivid, often horrifying, hallucinations are present but thought disorder, disorganized behavior, and affective flattening is absent),
- residual type (where positive symptoms are present at a low intensity only) and
- undifferentiated type (psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types has not been met). Symptoms may also be described as 'positive symptoms' (those additional to normal experience and behavior) and negative symptoms (the lack or decline in normal experience or behavior). 'Positive symptoms' describe psychosis and typically include delusions, hallucinations and thought disorder. 'Negative symptoms' describe inappropriate or nonpresent emotion, poverty of speech, and lack of motivation. In three-factor models of schizophrenia, a third symptom grouping, the so-called 'disorganization syndrome', is also given. This considers thought disorder and related disorganized behavior to be in a separate symptom cluster from delusions and hallucinations. Some people tend to classify the above two categories into types I and II (type-I with predominantly positive symptoms and type-II with predominantly negative symptoms) [http://homepage.psy.utexas.edu/homepage/class/Psy301/Salinas/sec3.2/Abnormal/12.html]. Some symptoms, such as social isolation, may be caused by a number of factors. One possible factor is impairment in social cognition, which is associated with schizophrenia, but isolation may also result from an individual reacting to psychotic symptoms (such as paranoia) or avoiding potentially stressful social situations which may exacerbate mental distress in some people. It is worth noting that many of the positive or psychotic symptoms may occur in a variety of disorders and not only in schizophrenia. The psychiatrist Kurt Schneider tried to list the particular forms of psychotic symptoms that he thought were particularly useful in distinguishing between schizophrenia and other disorders that could produce psychosis. These are called first rank symptoms or Schneiderian first rank symptoms and include delusions of being controlled by an external force, the belief that thoughts are being inserted or withdrawn from your conscious mind, the belief that your thoughts are being broadcast to other people and hearing hallucinated voices which comment on your thoughts or actions, or may have a conversation with other hallucinated voices. As with other diagnostic methods, the reliability of 'first rank symptoms' has been questioned, although they remain in use as diagnostic criteria in many countries.

Diagnostic issues and controversies

It has been argued that the diagnostic approach to schizophrenia is flawed, as it relies on an assumption of a clear dividing line between what is considered to be mental illness (fulfilling the diagnostic criteria) and mental health (not fulfilling the criteria). Recently it has been argued, notably by psychiatrist Jim van Os and psychologist Richard Bentall, that this makes little sense, as studies have shown that psychotic symptoms are present in many people who never become 'ill' in the sense of feeling distressed, becoming disabled in some way or needing medical assistance. Of particular concern is that the decision as to whether a symptom is present is a subjective decision by the person making the diagnosis or relies on an incoherent definition (for example, see the entries on delusions and thought disorder for a discussion of this issue). More recently, it has been argued that psychotic symptoms are not a good basis for making a diagnosis of schizophrenia as "psychosis is the 'fever' of mental illness — a serious but nonspecific indicator". Perhaps because of these factors, studies examining the diagnosis of schizophrenia have typically shown relatively low or inconsistent levels of diagnostic reliability. Most famously, David Rosenhan's 1972 study, published as On being sane in insane places, demonstrated that the diagnosis of schizophrenia was (at least at the time) often subjective and unreliable. More recent studies have found agreement between any two psychiatrists when diagnosing schizophrenia tends to reach about 65% at best. This, and the results of earlier studies of diagnostic reliability (which typically reported even lower levels of agreement) have led some critics to argue that the diagnosis of schizophrenia should be abandoned. Proponents have argued for a new approach that would use the presence of specific neurocognitive deficits to make a diagnosis. These often accompany schizophrenia and take the form of a reduction or impairment in basic psychological functions such as memory, attention, executive function and problem solving. It is these sorts of difficulties, rather than the psychotic symptoms (which can in many cases be controlled by antipsychotic medication), which seem to be the cause of most disability in schizophrenia. However, this argument is relatively new and it is unlikely that the method of diagnosing schizophrenia will change radically in the near future. The diagnostic approach to schizophrenia has also been opposed by the anti-psychiatry movement, who argue that classifying specific thoughts and behaviors as an illness allows social control of people that society finds undesirable but who have committed no crime. They argue that this is a way of unjustly classifying a social problem as a medical one to allow the forcible detention and treatment of people displaying these behaviors, which is something which can be done under mental health legislation in most western countries. An example of this can be seen in the Soviet Union, where an additional sub-classification of sluggishly progressing schizophrenia was created. Particularly in the RSFSR (Russian Soviet Federated Socialist Republic), this diagnosis was used for the purpose of silencing political dissidents or forcing them to recant their ideas by the use of forcible confinement and treatment. In 2000 similar concerns about the abuse of psychiatry to unjustly silence and detain members of the Falun Gong movement by the Chinese government led the American Psychiatric Association's Committee on the Abuse of Psychiatry and Psychiatrists to pass a resolution to urge the World Psychiatric Association to investigate the situation in China. Western psychiatric medicine tends to favor a definition of symptoms that depends on form rather than content (an innovation first argued for by psychiatrists Karl Jaspers and Kurt Schneider). Therefore, you should be able to believe anything, however unusual or socially unacceptable, without being diagnosed delusional, unless your belief is held in a particular way. In principle, this would stop people being forcibly detained or treated simply for what they believe. However, the distinction between form and content is not easy, or always possible, to make in practice (see delusion). This had led to accusations by anti-psychiatry, surrealist and mental health system survivor groups that psychiatric abuses exist to some extent in the West as well...

Causes

Genetic and environmental influences

While the reliability of the schizophrenia diagnosis introduces difficulties in measuring the relative effect of genes and environment (for example, symptoms overlap to some extent with severe bipolar disorder or major depression), there is evidence to suggest that genetic vulnerability and environmental stressors can act in combination to cause schizophrenia. The extent to which these factors influence the likelihood of being diagnosed with schizophrenia is debated widely, and currently, controversial. Schizophrenia is likely to be a disorder of complex inheritance (analogous to diabetes or high blood pressure). Thus, it is likely that several genes interact to generate risk for schizophrenia. This, combined with disagreements over which research methods are best, or how data from genetic research should be interpreted, has led to differing estimates over genetic contribution.

Genetic

Some researchers estimate schizophrenia to be highly heritable (some estimates are as high as 70%). However, genetic evidence for the role of the environment comes from the observation that one identical twin does not universally develop schizophrenia if the other one does. A recent review of the genetic evidence has suggested a 28% chance of one identical twin developing schizophrenia if the other already has it (see twin study). However, the estimates of heritability of schizophrenia from twin studies varies a great deal, with some notable studies showing rates as low as 11.0%–13.8% among monozygotic twins, and 1.8%–4.1% among dizygotic twins. A recent review of linkage studies listed seven genes as likely to be involved in the inheritance of schizophrenia or the risk of developing the disease. Evidence comes from research suggesting multiple chromosomal regions are transmitted to people who are later diagnosed as having schizophrenia. Some genetic association studies have demonstrated a relationship to a gene known as COMT that is involved in encoding the dopamine catabolic enzyme catechol-O-methyl transferase. This is particularly interesting because of the known link between dopamine function, psychosis, and schizophrenia.

Environmental

There is also considerable evidence indicating that stress may trigger episodes of schizophrenia psychosis. For example, emotionally turbulent families and stressful life events have been shown to be risk factors for relapses or triggers for episodes of schizophrenia. In common with other forms of mental illness, abuse as a child and early traumatic experience have also been suggested to be a risk factor for developing schizophrenia later in life , although the "bad parenting" theory of causation is now largely held in disrepute on the grounds that it overlooks the likelihood that the parental incompetences may have been a result of schizophrenia in the parents, and the disorder itself in the offspring was actually transmitted genetically from the parents. Factors such as poverty and discrimination may also be involved in increasing the risk of having a schizophrenic episode due to the high levels of stress that these lifestyles harbor. This may explain why minority communities have much higher rates of schizophrenia than when members of the same ethnic groups are resident in their home country. On the other hand, the "social drift hypothesis" suggests that people affected by schizophrenia may be less able to hold steady or demanding, higher-paying jobs, consigning them to lower incomes thereby increasing stress levels and leaving them suseptable to lapsing into a schizophrenic episode. One particularly stable and replicable finding has been the association between living in an urban environment and risk of developing schizophrenia, even after factors such as drug use, ethnic group and size of social group have been controlled for. A recent study of 4.4 million men and women in Sweden found a 68%–77% increased risk of psychosis for people living in the most urbanized environments, a significant proportion of which is likely to be accounted for by schizophrenia. One curious finding is that people diagnosed with schizophrenia are more likely to have been born in winter or spring (at least in the northern hemisphere). However, the effect is not large and it is still not clear why this may occur.

Neurobiological influences

Early neurodevelopment

It is also thought that processes in early neurodevelopment are important, particularly during pregnancy. For example, women who were pregnant during the Dutch famine of 1944, where many people were close to starvation, had a higher chance of having a child who would later develop schizophrenia. Similarly, studies of Finnish mothers who were pregnant when they found out that their husbands had been killed during the Winter War of 1939–1940 have shown that their children were much more likely to develop schizophrenia when compared with mothers who found out about their husbands' death after pregnancy, suggesting that even psychological trauma in the mother may have an effect. Some researchers have proposed that environmental influences during childhood also interact with neurobiological risk factors to influence the likelihood of developing schizophrenia later in life. The neurological development of children is considered sensitive to features of dysfunctional social settings, such as trauma, violence, lack of warmth in personal relationships and hostility. These have all been found to be risk factors for the later development of schizophrenia. It is thought that the effects of the childhood environment, favorable or unfavorable, interact with genetics and the processes of neurodevelopment, with long-term consequences for brain function. This is thought to influence the underlying vulnerability for psychosis later in life, particularly during the adult years. violence activated (red) during a working memory task, the greater the increase in abnormal dopamine activity in the striatum (green), thought to be related to the neurocognitive deficits in schizophrenia.]]

Role of dopamine

In adult life, particular importance has been placed upon the function (or malfunction) of dopamine in the mesolimbic pathway in the brain. This theory, known as the dopamine hypothesis of schizophrenia, largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, reduced psychotic symptoms. These drugs have now been developed further and antipsychotic medication is commonly used as a first line treatment. However, this theory is now thought to be overly simplistic as a complete explanation, partly because newer antipsychotic medication (called atypical antipsychotic medication) is equally effective as older medication (called typical antipsychotic medication), but also affects serotonin function and may have slightly less of a dopamine blocking effect. Psychiatrist David Healy has also argued that pharmaceutical companies have promoted certain oversimplified biological theories of mental illness to promote their own sales of biological treatments.

Role of glutamate and the NMDA receptor

Interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the development of schizophrenia. This theory has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that the glumatate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems of associated with the condition. The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can effect dopamine function, all of which have been implicated in schizophrenia, have suggested the glutamate hypothesis of schizophrenia as an increasingly popular explanation.

Structure and function of brain anatomy

Much recent research has focused on differences in structure or function in certain brain areas in people diagnosed with schizophrenia. Early evidence for differences in the neural structure came from the discovery of ventricular enlargement in people diagnosed with schizophrenia, for whom negative symptoms were most prominent. However, this finding has not proved particularly reliable on the level of the individual person, with considerable variation between patients. More recent studies have shown a large number of differences in brain structure between people with and without diagnoses of schizophrenia. However, as with earlier studies, many of these differences are only reliably detected when comparing groups of people, and are unlikely to predict any differences in brain structure of an individual person with schizophrenia. Studies using neuropsychological tests and brain scanning technologies such as fMRI and PET to examine functional differences in brain activity have shown that differences seem to most commonly occur in the frontal lobes, hippocampus, and temporal lobes. These differences are heavily linked to the neurocognitive deficits which often occur with schizophrenia, particularly in areas of memory, attention, problem solving, executive function and social cognition. Electroencephalograph (EEG) recordings of persons with schizophrenia performing perception oriented tasks showed an absence of gamma band activity in the brain, indicating weak integration of critical neural networks in the brain. Those who experienced intense hallucinations, delusions and disorganized thinking showed the lowest frequency synchronization. None of the drugs taken by the persons scanned had moved neural synchrony back into the gamma frequency range. Gamma band and working memory alterations may be related to alterations in interneurons that produced the neurotransmitter GABA. Alterations in a subclass of GABAergic interneurons which produce the calcium binding protein parvalbumin have been shown to exist in the DLPFC in schizophrenia.

Incidence and prevalence

Schizophrenia is typically diagnosed in late adolescence or early adulthood. It is found approximately equally in men and women, though the onset tends to be later in women, who also tend to have a better course and outcome. The lifetime prevalence of schizophrenia is commonly given at 1%; however, a recent review of studies from around the world estimated it to be 0.55%. The same study also found that prevalence may vary greatly from country to country, despite the received wisdom that schizophrenia occurs at the same rate throughout the world. It is worth noting however, that this may be in part due to differences in the way schizophrenia is diagnosed. The incidence of schizophrenia was given as a range of between 7.5 and 16.3 cases per year per 100,000 population. Schizophrenia is also a major cause of disability. In a recent 14-country study, active psychosis was ranked the third most disabling condition after quadriplegia and dementia and before paraplegia and blindness.

Treatment

Medication and hospitalization

The first line treatment for schizophrenia is usually the use of antipsychotic medication. The newer atypical antipsychotic medications (such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) are preferred over older typical antipsychotic medications (such as chlorpromazine and haloperidol) due to their favorable side-effect profile. Compared to the typical antipsychotics, the atypicals are associated with a lower incident rate of extrapyramidal side-effects (EPS) and tardive dyskinesia (TD). It is still unclear whether newer drugs reduce the chances of developing the rare but potentially life-threatening neuroleptic malignant syndrome (NMS). While the atypical antipsychotics are associated with less EPS and TD than the conventional antipsychotics, some of the agents in this class (especially olanzapine and clozapine) appear to be associated with metabolic side effects such as weight gain, hyperglycemia and hypertriglyceridemia that must be considered when choosing appropriate pharmacotherapy. Atypical and typical antipsychotics are generally thought to be equivalent for the treatment of the positive symptoms of schizophrenia. It has been suggested by some researchers that the atypicals have some beneficial effects on negative symptoms and cognitive deficits associated with schizophrenia, although the clinical significance of these effects has yet to be established. However, recent reviews have suggested that typical antipsychotics, when dosed conservatively, may have similar effects to atypicals. The atypical antipsychotics are much more costly as they are still within patent, whereas the older drugs are available in inexpensive generic forms. Aripiprazole, a drug from a new class of antipsychotic drugs (variously named 'dopamine system stabilizers' or 'partial dopamine agonists'), has recently been developed. Early research suggests that it may be a safe and effective treatment for schizophrenia. Hospitalization may occur with severe episodes. This can be voluntary or (if mental health legislation allows it) involuntary (called civil or involuntary commitment). Mental health legislation may also allow people to be treated against their will. However, in many countries such legislation does not exist, or does not have the power to enforce involuntary hospitalization or treatment.

Therapy and community support

Psychotherapy or other forms of talk therapy may be offered, with cognitive behavioral therapy being the most frequently used. This may focus on the direct reduction of the symptoms, or on related aspects, such as issues of self-esteem, social functioning, and insight. Although the results of early trials with cognitive behavioral therapy (CBT) were inconclusive, more recent reviews suggest that CBT can be an effective treatment for the psychotic symptoms of schizophrenia. A relatively new approach has been the use of cognitive remediation therapy, a technique aimed at remediating the neurocognitive deficits sometimes present in schizophrenia. Based on techniques of neuropsychological rehabilitation, early evidence has shown it to be cognitively effective, with some improvements related to measurable changes in brain activation as measured by fMRI. Electroconvulsive therapy (also known as ECT or 'electroshock therapy') may be used in countries where it is legal. It is not considered a first line treatment but may be prescribed in cases where other treatments have failed. Psychosurgery has now become a rare procedure and is not a recommended treatment for schizophrenia. Other support services may also be available, such as drop-in centers, visits from members of a 'community mental health team', and patient-led support groups. In recent years the importance of service-user led recovery based movements has grown substantially throughout Europe and America. Groups such as the Hearing Voices Network and more recently, the Paranoia Network, have developed a self-help approach that aims to provide support and assistance outside of the traditional medical model adopted by mainstream psychiatry. By avoiding framing personal experience in terms of criteria for mental illness or mental health, they aim to destigmatize the experience and encourage individual responsibility and a positive self-image. In many non-Western societies, schizophrenia may be treated with more informal, community-led methods. A particularly sobering thought for Western psychiatry is that the outcome for people diagnosed with schizophrenia in non-Western countries may actually be much better than for people in the West. The reasons for this recently discovered fact are still far from clear, although cross-cultural studies are being conducted to find out why.

Prognosis

Prognosis for any particular individual affected by schizophrenia is particularly hard to judge as treatment and access to treatment is continually changing, as new methods become available and medical recommendations change. However, retrospective studies have shown that about a third of people make a full recovery, about a third show improvement but not a full recovery, and a third remain ill. The World Health Organization conducted two long-term follow-up studies involving more than 2,000 people suffering from schizophrenia in different countries, and discovered these patients have much better long-term outcomes in poor countries (India, Colombia and Nigeria) than in rich countries (USA, UK, Ireland, Denmark, Czechoslovakia, Japan, and Soviet Union), despite the fact antipsychotic medication is typically not widely available in poorer countries. In a study of over 168,000 Swedish citizens undergoing psychiatric treatment, schizophrenia was associated with an average life expectancy of approximately 80-85% of that of the general population. Women with a diagnosis of schizophrenia were found to have a slightly better life expectancy than that of men, and as a whole, a diagnosis of schizophrenia was associated with a better life expectancy than substance abuse, personality disorder, heart attack and stroke. There is an extremely high suicide rate associated with schizophrenia. A recent study showed that 30% of patients diagnosed with this condition had attempted suicide at least once during their lifetime. Another study suggested that 10% of persons with schizophrenia die by suicide.

Schizophrenia and drug use

The relationship between schizophrenia and drug use is complex, meaning that a clear causal connection between drug use and schizophrenia has been difficult to tease apart. There is strong evidence that using certain drugs can trigger either the onset or relapse of schizophrenia in some people. It may also be the case, however, that people with schizophrenia use drugs to overcome negative feelings associated with the commonly prescribed antipsychotic medication, and the disorder itself, where negative emotion, paranoia and anhedonia are all considered to be core features.

Hallucinogens

Schizophrenia can sometimes be triggered by heavy use of stimulant or hallucinogenic drugs, although some claim that a predisposition towards developing schizophrenia is needed for this to occur. There is also some evidence suggesting that people suffering schizophrenia but responding to treatment can have relapse because of subsequent drug use. Drugs such as methamphetamine, ketamine, PCP and LSD have been used to mimic schizophrenia for research purposes, although this has now fallen out of favor with the scientific research community, as the differences between the drug induced states and the typical presentation of schizophrenia have become clear. Hallucinogenic drugs were also briefly tested as possible treatments for schizophrenia by psychiatrists such as Humphry Osmond and Abram Hoffer in the 1950s. Ironically, it was mainly for this experimental treatment of schizophrenia that LSD administration was legal, briefly before its use as a recreational drug led to its criminalization.

Cannabis

There is increasing evidence that cannabis use can be a contributing trigger to developing schizophrenia. Some studies suggest that cannabis is neither a sufficient nor necessary factor in developing schizophrenia, but that cannabis may significantly increase the risk of developing schizophrenia and may be, among others, a significant causal factor. Some previous research in this area has been questioned, however, as it has often not been clear whether cannabis is playing a role as a cause, or whether schizophrenia may cause cannabis use, or both phenomena might share a common cause. A recent review of studies from which a causal contribution to schizophrenia can be assessed, has suggested that cannabis doubles the risk of developing schizophrenia on the individual level, and may be responsible for up to 8% of cases in the population.

Tobacco

It has been noted that the majority of people with schizophrenia (estimated between 75% and 90%) smoke tobacco. However, people diagnosed with schizophrenia have a much lower than average chance of getting and dying from lung cancer. While the reason for this is unknown, it may be because of a genetic resistance to the cancer, a side-effect of drugs being taken, or a statistical effect of increased likelihood of dying from causes other than lung cancer. It is argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine. A recent study of over 50,000 Swedish conscripts found that there was a small but significant protective effect of smoking cigarettes on the risk of developing schizophrenia later in life. Whilst the authors of the study stressed that the risks of smoking far outweigh these minor benefits, this study provides further evidence for the 'self-medication' theory of smoking in schizophrenia and may give clues as to how schizophrenia might develop at the molecular level. Furthermore, many people with schizophrenia have smoked tobacco products long before they are diagnosed with the illness, and some groups advocate that the chemicals in tobacco have actually contributed to the onset of the illness and have no benefit of any kind.

Schizophrenia and violence

Violence perpetrated by people with schizophrenia

Although schizophrenia is sometimes associated with violence in the media, only a minority of people with schizophrenia become violent, and only a minority of people who commit criminal violence have been diagnosed with schizophrenia. Research has suggested that schizophrenia is associated with a slight increase in risk of violence, although this risk is largely due to a small sub-group of individuals for whom violence is associated with concurrent substance abuse, active delusional beliefs of threat or persecution, and ceasing effective treatment for previous violent behavior. For the most serious acts of violence, long-term independent studies of convicted murderers in both New Zealand and Sweden found that 8.7%–8.9% had been given a previous diagnosis of schizophrenia. There is some evidence to suggest that in some people, the drugs used to treat schizophrenia may produce an increased risk for violence, largely due to agitation induced by akathisia, a side effect sometimes associated with antipsychotic medication. Similarly, abuse experienced in childhood may contribute both to a slight increase in risk for violence in adulthood, as well as the development of schizophrenia.

Violence against people with schizophrenia

Research has shown that a person diagnosed with schizophrenia is more likely to be a victim of violence (4.3% in a one month period) than the perpetrator.

Alternative approaches to schizophrenia

An approach broadly known as the anti-psychiatry movement, notably most active in the 1960s, has opposed the orthodox medical view of schizophrenia as an illness. Psychiatrist Thomas Szasz has argued that psychiatric patients are not ill but are just individuals with unconventional thoughts and behavior that make society uncomfortable. He argues that society unjustly seeks to control such individuals by classifying their behavior as an illness and forcibly treating them as a method of social control. An important but subtle point is that Szasz has never denied the existence of the phenomena that mainstream psychiatry classifies as an illness (such as delusions, hallucinations or mood changes) but simply does not believe that they are a form of illness. Similarly, psychiatrist R. D. Laing has argued that the symptoms of what is normally called mental illness are just comprehensible reactions to impossible demands that society and particularly family life places on some sensitive individuals. Laing was revolutionary in valuing the content of psychotic experience as worthy of interpretation, rather than considering it simply as a secondary but essentially meaningless marker of underlying psychological or neurological distress. It is worth noting that neither Szasz nor Laing ever considered themselves to be "anti-psychiatry" in the sense of being against psychiatric treatment, but simply believed that it should be conducted between consenting adults, rather than imposed upon anyone against their will. In the 1976 book The Origin of Consciousness in the Breakdown of the Bicameral Mind, psychologist Julian Jaynes proposed that until the beginning of historic times, schizophrenia or a similar condition was the normal state of human consciousness. This would take the form of a "bicameral mind" where a normal state of low affect, suitable for routine activities, would be interrupted in moments of crisis by "mysterious voices" giving instructions, which early people characterized as interventions from the gods. This theory was briefly controversial. Continuing research has failed to either further confirm or refute the thesis. Psychiatrist Tim Crow has argued that schizophrenia may be the evolutionary price we pay for a left brain hemisphere specialization for language. Since psychosis is associated with greater levels of right brain hemisphere activation and a reduction in the usual left brain hemisphere dominance, our language abilities may have evolved at the cost of causing schizophrenia when this system breaks down. Researchers into shamanism have speculated that in some cultures schizophrenia or related conditions may predispose an individual to becoming a shaman. Certainly, the experience of having access to multiple realities is not uncommon in schizophrenia, and is a core experience in many shamanic traditions. Equally, the shaman may have the skill to bring on and direct some of the altered states of consciousness psychiatrists label as illness. (See anti-psychiatry.) Speculations regarding primary and important religious figures as having schizophrenia abound. Some commentators have endorsed the idea that major religious figures experienced psychosis, heard voices and displayed delusions of grandeur. Alternative medicine tends to hold the view that schizophrenia is primarily caused by imbalances in the body's reserves and absorption of dietary minerals, vitamins, fats, and/or the presence of excessive levels of toxic heavy metals. The body's adverse reactions to gluten are also strongly implicated in some alternative theories (see gluten-free, casein-free diet). One theory put forward by psychiatrists E. Fuller Torrey and R.H. Yolken is that the parasite Toxoplasma gondii leads to some, if not many, cases of schizophrenia. An additional approach is suggested by the work of Richard Bandler who argues that "The usual difference between someone who hallucinates and someone who visualizes normally, is that the person who hallucinates doesn't know he's doing it or doesn't have any choice about it." (Time for a Change

Carbatrol

Mechanisms

Side Effects

History

Reference

External links

Anticonvulsant

Aldehydes

Aromatic Allylic Alcohols

Barbiturates

Benzodiazepines

Bromides

Carbamates

Carboxamides

Fatty Acids

Fructose Derivatives

GABA Analogs

Hydantoins

Oxazolidinediones

Propionates

Pyrimidinediones

Pyrrolidines

Succinimides

Sulfonamides

Triazines

Ureas

Valproylamides (Amide Derivatives of Valproate)

References and end notes

Mood stabilizer

References

External link

Epilepsy

Causes

Diagnosis

Types of seizure

Seizure Syndromes

Treatment

Responding to a seizure

Pharmacologic treatment

Surgical Treatment

Other Treatment

History and Stigma

Legal implications

Important investigators of epilepsy

See also

References

External links

Worldwide non-profit organizations

Regional epilepsy organizations

Schizophrenia

Overview

History

Diagnosis

Diagnosis and presentation (signs and symptoms)

Diagnostic issues and controversies

Causes

Genetic and environmental influences

Genetic

Environmental

Neurobiological influences

Early neurodevelopment

Role of dopamine

Role of glutamate and the NMDA receptor

Structure and function of brain anatomy

Incidence and prevalence

Treatment

Medication and hospitalization

Therapy and community support

Prognosis

Schizophrenia and drug use

Hallucinogens

Cannabis

Tobacco

Schizophrenia and violence

Violence perpetrated by people with schizophrenia

Violence against people with schizophrenia

Alternative approaches to schizophrenia