Antipsychotic

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Antipsychotics are a group of drugs commonly but not exclusively used to treat psychosis. Conditions for which antipsychotic drugs might be used include schizophrenia, bipolar disorder, mania, and delusional disorder. Over time different classes of antipsychotics have been developed. A first generation of antipsychotics, known as typical antipsychotics, were discovered in the 1950s. Most of the drugs in the second generation of antipsychotics, known as atypical antipsychotics, have more recently been developed and come into use. Both classes of medication tend to block receptors in dopamine pathways in the brain. A number of side effects have been observed in relation to specific medications, including weight gain, agranulocytosis, tardive dyskinesia, tardive akathisia and tardive psychoses. The relative efficacy of typical versus atypical antipsychotics along various dimensions has recently been a subject of study and to a certain extent remains to be understood.

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[edit] Terminology

Antipsychotics are also referred to as neuroleptic drugs. The word neuroleptic is derived from Greek: "νεύρον" (originally meaning sinew but today 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.[citation needed] 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.

[edit] 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 since the patient becomes deenergized or deenervated, will or volition is crushed, and passivity and docility are induced therefore the patient complains less and becomes more manageable, although this is controversial.

[edit] 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.

[edit] Common antipsychotics

Chlorpromazine.
Chlorpromazine.
Haloperidol.
Haloperidol.
Quetiapine.
Quetiapine.

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

[edit] First generation antipsychotics

[edit] Butyrophenones

[edit] Phenothiazines

[edit] Thioxanthenes

[edit] Second generation antipsychotics

  • 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 or Anxiety Disorder.
  • 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).

[edit] Third generation antipsychotics

  • 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.[1]

[edit] 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. [2]

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.

Metabotropic glutamate receptor 2 agonism has been seen as a promissing strategy in the development of novel antipsychotics.[3] When tested in patients, the research substance LY2140023 yielded promising results and had few side effects. The active metabolite of this prodrug targets the brain glutamate receptors mGluR2/3 rather than dopamine receptors.[4] It is currently in phase-2 clinical testing (2007).

[edit] 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.[5]

[edit] Side effects

Antipsychotics are associated with a range of side effects. Around two-thirds of people in controlled drug trials discontinue antipsychotics, partly due to adverse effects.[citation needed] Extrapyramidal reactions include tardive psychosis, acute dystonias, akathisia, parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, and hyperprolactinaemia.

From a subjective perspective, antipsychotics heavily influence one's perceptions of pleasurable sensations, causing a severe reduction in feelings of desire, motivation, pensive thought, and awe. This does not coincide with the apathy and lack of motivation experienced by the negative symptoms of schizophrenia. Detrimental effects on short term memory, which affect the way one figures and calculates (although this also may be purely subjective), may also be observed on high enough dosages. These are all the reasons why they are thought to affect "creativity". Also, for some schizophrenics, too much stress will cause them to "relapse". However, in general, too much stress will also put the patient into a deep drowsy state, even to the point of sleep, while on antipsychotic medications.

Also, this may be unique to the author, but antipsychotics have a detrimental effect on short term memory.

Following are details concerning some of the side effects of antipsychotics:

  • 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, which 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.[citation needed]
  • 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.
  • A potentially serious side effect of many antipsychotics is that they tend to lower an individual's 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 antipsychotic side effect is deterioration of teeth due to a lack of saliva.[citation needed]
  • 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.
  • Loss of glial cells was observed in monkeys[6] and signs of neuron death were detected in women[7].

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

There is a possibility that the risk of tardive dyskinesia can be reduced by combining the anti-psychotics with diphenhydramine or benztropine, although this remains to be established. Central nervous system damage is also associated with irreversible tardive akathisia and/or tardive dysphrenia.

[edit] 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.[8][9] 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—prescribing two or more antipsychotics at the same time for an individual—is said to be a frequent practice but not necessarily evidence-based.[10]

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.[11][12] 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.[13] 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.[14] Some argue that, overall, the evidence suggests that antipsychotics only help if they are used selectively and are gradually withdrawn as soon as possible.[15]

A dose response effect has been found in one study from 1971 between increasing neuroleptic dose and increasing number of psychotic breaks.[16][verification needed]

[edit] 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, the 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.[17] 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.[18] 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. [19] 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.

[edit] See also

[edit] References

  1. ^ Swainston, Harrison T.; Perry, C.M. (2004). "Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder.". Drugs 64 (15): 1715-1736. PMID 15257633
  2. ^ Zuardi, A.W; J.A.S. Crippa, J.E.C. Hallak, F.A. Moreira, F.S. Guimarães (2006). "Cannabidiol as an antipsychotic drug". Brazilian Journal of Medical and Biological Research 39: 421-429. ISSN 0100-879X ISSN 0100-879X. 
  3. ^ PMID 17526600 PMID 18424625 PMID 18297054
  4. ^ BBC NEWS, Schizophrenia trials 'promising'
  5. ^ Murphy, B.P.; Chung YC, Park TW, McGorry PD (12 2006). "Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review". Schizophrenia Research 88 (1-3): 5-25. PMID 16930948
  6. ^ Effect of Chronic Exposure to Antipsychotic Medication on Cell Numbers in the Parietal Cortex of Macaque Monkeys, by Glenn T Konopaske, Karl-Anton Dorph-Petersen, Joseph N Pierri, Qiang Wu, Allan R Sampson and David A Lewis, Neuropsychopharmacology, 2006, 1-8.
  7. ^ The influence of psychotropic drugs on cerebral cell female neurovulnerability to antipsychotics, by Raphael M. Bonelli, Peter Hofmann, Andreas Aschoff, Gerald Niederwieser, Clemens Heuberger, Gustaf Jirikowski and Hans-Peter Kapfhammer, International Clinical Psychopharmacology 2005, 20:145-149
  8. ^ American Psychiatric Association (2004) Practice Guideline for the Treatment of Patients With Schizophrenia. Second Edition.
  9. ^ The Royal College of Psychiatrists & The British Psychological Society (2003). Schizophrenia. Full national clinical guideline on core interventions in primary and secondary care (PDF). London: Gaskell and the British Psychological Society.
  10. ^ Patrick V, Levin E, Schleifer S. (2005) Antipsychotic polypharmacy: is there evidence for its use? J Psychiatr Pract. 2005 Jul;11(4):248-57. PMID 16041235
  11. ^ Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper J, Day R, Bertelsen A. "Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study". Psychol Med Monogr Suppl 20: 1-97. PMID 1565705. 
  12. ^ Hopper K, Wanderling J (2000). Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: results from ISoS, the WHO collaborative followup project. International Study of Schizophrenia. Schizophrenia Bulletin, 26 (4), 835–46. PMID 11087016
  13. ^ Moncrieff J. (2006) Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatrica Scandinavica Jul;114(1):3-13. PMID 16774655
  14. ^ Harrow M, Jobe TH. (2007) Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. J Nerv Ment Dis. May;195(5):406-14. PMID 17502806
  15. ^ Whitaker R. (2004) The case against antipsychotic drugs: a 50-year record of doing more harm than good. Med Hypotheses. 2004;62(1):5-13. PMID 14728997
  16. ^ Prien R, Levine J, Switalski R (1971). "Discontinuation of chemotherapy for chronic schizophrenics". Hosp Community Psychiatry 22 (1): 4-7. PMID 4992967. 
  17. ^ Lieberman J et al (2005). "Effectiveness of antipsychotic drugs in patients with chronic schizophrenia". N Engl J Med 353 (12): 1209-23. PMID 16172203. 
  18. ^ Stroup T et al (2006). "Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic". Am J Psychiatry 163 (4): 611-22. doi:10.1176/appi.ajp.163.4.611. PMID 16585435. 
  19. ^ McEvoy J et al (2006). "Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia that did not respond to prior atypical antipsychotic treatment". Am J Psychiatry 163 (4): 600-10. PMID 16585434. 
  • Jones, H. M., & Pilowsky, L. S. (2002) Dopamine and antipsychotic drug action revisited. British Journal of Psychiatry, 181, 271-275.
  • Jablensky, A. (1992). Schizophrenia: manifestations, incidence and course in different cultures, A World Health Organization ten-country study, Psychological Medicine, 20 1-95.
  • Prien, R. , Levine, J., & Switalski, R. (1971). Discontinuation of chemotherapy for chronic schizophrenics. Hospital & Community Psychiatry, 22(1), 4-7.

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