Antipsychotics

Overview
The term antipsychotic is applied to a group of drugs commonly but not exclusively used to treat psychosis. Common conditions with which antipsychotics might be used include schizophrenia, bipolar disorder, mania and delusional disorder.

Terminology
Antipsychotics are also referred to as neuroleptic drugs, neuroleptics. The word neuroleptic is derived from Greek: "νεύρο" referring to the nerves and "λαμβάνω" meaning take hold of. Thus, the word means taking hold of one's nerves. This term reflects the drugs' ability to make movement more difficult and sluggish, which clinicians previously believed indicated that a dose was high enough. The lower doses used currently have resulted in reduced incidence of motor side effects and sedation, and the term is less commonly used than in the past.

Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics. There are also dopamine partial agonists, which are often categorized as atypicals.

Typical antipsychotics are also sometimes referred to as major tranquilizers, because some of them can tranquilize and sedate. This term is increasingly disused, as the terminology implies a connection with benzodiazepines ("minor" tranquilizers) when none exists.

Usage
Common conditions with which antipsychotics might be used include schizophrenia, mania, and delusional disorder. They might be used to counter psychosis associated with a wide range of other diagnoses. Antipsychotics may also be used in mood disorder (e.g., bipolar disorder) even when no signs of psychosis are present. In addition, these drugs are used to treat non-psychotic disorders. For example, some antipsychotics (haloperidol, pimozide) are used off-label to treat Tourette syndrome, whereas abilify is prescribed in some cases of Asperger's syndrome.

In routine clinical practice, antipsychotics may be used as part of risk management, and to control difficult patients, although this is controversial.

History
The original antipsychotic drugs were happened upon largely by chance and were tested empirically for their effectiveness.

The first antipsychotic was chlorpromazine, which was developed as a surgical anesthetic. It was first used on psychiatric patients in the belief that it would have a calming effect. However, the drug soon appeared to reduce psychosis beyond this calming effect, and now some believe that it causes a reduction of psychosis unrelated to the sedating effect of the medication. It was introduced for the treatment of psychosis during the period when lobotomy was a common treatment and was hailed as a "cure" for schizophrenia. It was then touted to provide a "chemical lobotomy," causing similar neurological effects without requiring surgery.

The newer atypical antipsychotics are, it is claimed, rationally-designed drugs in which a theoretical understanding of both the condition to be treated and the effect of certain molecules on the body is used to develop potential new drug candidates. However, continued off-label use of the newer drugs indicates that old-fashioned empirical drug discovery is still important in evaluating this class of medication.

Common antipsychotic drugs
Commonly used antipsychotic medications are listed below by drug group. Trade names appear in parentheses.

Phenothiazines

 * Chlorpromazine (Thorazine)
 * Fluphenazine (Prolixin) - Available in decanoate (long-acting) form
 * Perphenazine (Trilafon)
 * Prochlorperazine (Compazine)
 * Thioridazine (Mellaril)
 * Trifluoperazine (Stelazine)
 * Mesoridazine
 * Promazine
 * Triflupromazine (Vesprin)
 * Levomepromazine (Nozinan)
 * Promethazine (Phenergan)

Thioxanthenes

 * Chlorprothixene
 * Flupentixol (Depixol and Fluanxol)
 * Thiothixene (Navane)
 * Zuclopenthixol (Clopixol and Acuphase)

Butyrophenones

 * Haloperidol (Haldol) - Available in decanoate (long-acting) form
 * Droperidol
 * Pimozide (Orap) - Used to treat Tourette syndrome
 * Melperone
 * Benperidol
 * Triperidol

Second Generation Anti-psychotics

 * Clozapine (Clozaril) - Requires weekly to biweekly CBC (FBC) because of risk of agranulocytosis (a severe decrease of white blood cells).
 * Olanzapine (Zyprexa) - Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Dosing 2.5 to 20 mg per day. Comes in a form that quickly dissolves in the mouth (Zyprexa Zydis). May cause appetite increase, weight gain, and altered glucose metabolism leading to an increased risk of diabetes mellitus.
 * Risperidone (Risperdal) - Dosing 0.25 to 6 mg per day and is titrated upward; divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Available in long-acting form (Risperdal Consta that is administered every 2 weeks; usual dose is 25 mg). Comes in a form that quickly dissovles in the mouth (Risperdal M-Tab). Used off-label to treat Tourette Syndrome.
 * Quetiapine (Seroquel) - Used primarily to treat bipolar disorder and schizophrenia, and "off-label" to treat chronic insomnia and restless legs syndrome; it is a powerful sedative (if it is used to treat sleep disorders and is not effective at 200 mg, it is not going to be effective in this regard). Dosing starts at 25 mg and continues up to 800 mg maximum per day, depending on the severity of the symptom(s) being treated. Users typically take smaller doses during the day for the neuroleptic properties and larger dose at bedtime for the sedative effects, or divided in two equal high doses every 12 hours (75 - 400 mg bid).
 * Ziprasidone (Geodon) - Now (2006) approved to treat bipolar disorder. Dosing 20 mg twice daily initially up to 80 mg twice daily. Prolonged QT interval a concern; watch closely with patients that have heart disease; when used with other drugs that prolong QT interval potentially life-threatening.
 * Amisulpride (Solian) - Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have anti-depressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social anxiety disorder. In one particular study, amisulpride was found to have greater efficacy than fluoxetine in decreasing anxiety. At present, amisulpride is approved in Europe, Australia, and other countries for use in schizophrenia, and is approved and marketed in lower dosages in some countries for treating dysthymia (such as in Italy as Deniban). Amisulpride has not been approved by the FDA for use in the United States.
 * Paliperidone (Invega) - Derivative of risperidone. Approved in December 2006.
 * Dopamine partial agonists:
 * Under clinical development - Bifeprunox; norclozapine (ACP-104).

Third Generation Anti-psychotics

 * Aripiprazole (Abilify) - Dosing 1 mg up to maximum of 30 mg has been used. Mechanism of action is thought to reduce susceptibility to metabolic symptoms seen in some other atypical antipsychotics.

Other options

 * Symbyax - A combination of olanzapine and fluoxetine used in the treatment of bipolar depression.
 * Tetrabenazine (Nitoman in Canada and Xenazine in New Zealand and some parts of Europe) is similar in function to antipsychotic drugs, though is not, in general, considered an antipsychotic itself. This is likely due to its main usefulness being the treatment of hyperkinetic movement disorders such as Huntington's Disease and Tourette syndrome, rather than for conditions such as schizophrenia. Also, rather than having the potential to cause tardive dyskinesia, which most antipsychotics have, tetrabenazine can actually be an effective treatment for the condition.
 * Cannabidiol One of the main psychoactive components of cannabis. A recent study has shown cannabidiol to be as effective as atypical antipsychotics in treating schizophrenia.

The most common typical antipsychotic drugs are now off-patent, meaning any pharmaceutical company is legally allowed to produce cheap generic versions of these medications. While this makes them cheaper than the atypical drugs that are still manufactured under patent constraints, atypical drugs are preferred as a first-line treatment because they are believed to have fewer side effects and seem to have additional benefits for the 'negative symptoms' of schizophrenia, a typical condition for which they might be prescribed.

"LY2140023"

A new schizophrenia drug "LY2140023" yielded promising results, as it targets in the brain – glutamate receptors rather than dopamine and had few side effects. The Nature Medicine study, by drug firm Eli Lilly found it promising and Dr.Sandeep Patil's team proved that LY2140023 appear to work as antipsychotics when tested upon rodents.

Drug action
All antipsychotic drugs tend to block D2 receptors in the dopamine pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. It is the blockade of dopamine receptors in this pathway that is thought to control psychotic experiences.

Typical antipsychotics are not particularly selective and also block Dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some of the unwanted side effects that the typical antipsychotics can produce (see below). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side effects.

Atypical antipsychotic drugs have a similar blocking effect on D2 receptors. Some also block or partially block serotonin receptors (particularly 5HT2A, C and 5HT1A receptors):ranging from risperidone, which acts overwhelmingly on serotonin receptors, to amisulpride, which has no serotonergic activity. The additional effects on serotonin receptors may be why some of them can benefit the 'negative symptoms' of schizophrenia.

Side-effects
Antipsychotics are associated with a range of side effects. It is well recognized that many people (around two-thirds in controlled drug trials) discontinue antipsychotics, partly due to adverse effects.

Extrapyramidal reactions include tardive psychosis, acute dystonias, akathisia, parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, and hyperprolactinaemia.

The atypical antipsychotics (especially olanzapine) seem to cause weight gain more commonly than the typical antipsychotics. The well-documented metabolic side effects associated with weight gain include diabetes that, frequently, can be life-threatening.

Clozapine also has a risk of inducing agranulocytosis, a potentially dangerous reduction in the number of white blood cells in the body. Because of this risk, patients prescribed clozapine may need to have regular blood checks to catch the condition early if it does occur, so the patient is in no danger.

One of the more serious of these side effects is tardive dyskinesia, in which the sufferer may show repetitive, involuntary, purposeless movements often of the lips, face, legs, or torso. It is believed that there is a greater risk of developing tardive dyskinesia with the older, typical antipsychotic drugs, although the newer antipsychotics are now also known to cause this disorder. It is believed by some that the risk of tardive dyskinesia can be reduced by combining the anti-psychotics with diphenhydramine or benztropine, though this has not been established. Central nervous system damage is also associated with irreversible tardive akathisia and/or tardive dysphrenia.

Another antipsychotic side effect is deterioration of teeth due to a lack of saliva.

A potentially serious side effect of many antipsychotics is that they tend to lower an individuals seizure threshold. Chlorpromazine and clozapine, in particular, have a relatively high seizurogenic potential. Fluphenazine, haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution should be exercised in individuals that have a history of seizurogenic conditions (such as epilepsy, or brain damage).

Another serious side effect is neuroleptic malignant syndrome, in which the drugs appear to cause the temperature regulation centers to fail, resulting in a medical emergency, as the patient's temperature suddenly increases to dangerous levels.

Another problematic side effect of antipsychotics is dysphoria.

Some people suffer few of the obvious side effects from taking antipsychotic medication, whereas others may have serious adverse effects. Some side effects, such as subtle cognitive problems, may go unnoticed.

Efficacy
There have been a large number of studies of the efficacy of typical antipsychotics, and an increasing number on the more recent atypical antipsychotics.

The American Psychiatric Association and the UK National Institute for Health and Clinical Excellence recommend antipsychotics for managing acute psychotic episodes and for preventing relapse. They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible.

Antipsychotic polypharmacy&mdash;prescribing two or more antipsychotics at the same time for an individual&mdash;is said to be a frequent practice but not necessarily evidence-based.

Some doubts have been raised about the long-term effectiveness of antipsychotics because two large international World Health Organization studies found individuals diagnosed with schizophrenia tend to have better long-term outcomes in developing countries (where there is lower availability and use of antipsychotics) than in developed countries. The reasons for the differences are not clear, however, and various explanations have been suggested.

Some argue that the evidence for antipsychotics from withdrawal-relapse studies may be flawed, because they do not take into account that antipsychotics may sensitize the brain and provoke psychosis if discontinued. Evidence from comparison studies indicates that at least some individuals recover from psychosis without taking antipsychotics, and may do better than those that do take antipsychotics. Some argue that, overall, the evidence suggests that antipsychotics only help if they used selectively and are gradually withdrawn as soon as possible. A dose response effect has been found in one study from 1971 between increasing neuroleptic dose and increasing number of psychotic breaks.

Typical versus atypical
While the atypical, second-generation medications were marketed as offering greater efficacy in reducing psychotic symptoms while reducting side effects (and extra-pyramidal symptoms in particular) than typical medications, these results showing these effects often lack robustness. To remediate this problem, the NIMH conducted a recent multi-site, double-blind study (the CATIE project), which was published in 2005. This study compared several atypical antipsychotics to an older typical antipsychotic, perphenazine, among 1493 persons with schizophrenia. Perphenazine was chosen because of its lower potency and moderate side effect profile. The study found that only olanzapine outperformed perphenazine in the researchers' principal outcome, the discontinuation rate. The authors also noted the apparent superior efficacy of olanzapine to the other drugs for greater reduction in psychopathology, longer duration of successful treatment, and lower rate of hospitalizations for an exacerbation of schizophrenia. In contrast, no other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on those measures. Olanzapine, however, was associated with relatively severe metabolic effects: Subjects with olanzapine showed a major weight gain problem and increases in glucose, cholesterol, and triglycerides. The average weight gain (1.1 kg/month, or 44 pounds for the 18 months that lasted the study) casts serious doubt on the potentiality of long-term use of this drug. Perphenazine did not create more extrapyramidal side effect as measured by rating scales (a result supported by a meta-analysis by Dr. Leucht published in Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8 percent vs. 2 percent to 4 percent, P=0.002).

A phase 2 part of this study roughly replicated these findings. This phase consisted on a second randomization of the patients that discontinuated the taking of medication in the first phase. Olanzapine was again the only medication to stand out in the outcome measures, although the results did not always reach statistical significance, in part to the decrease of power. Perphenazine again did not create more extrapyramidal effects.

A subsequent phase was conducted. This phase innovated in allowing clinicians to offer clozapine. Clozapine indeed proved to be more effective at reducing medication drop-outs than other neuroleptic agents. Researchers also observed a trend showing clozapine with a greater reduction of symptoms. However, the potential of clozapine to cause toxic side effects, including agranulocytosis, limits the prescription to persons with schizophrenia.