The term antipsychotic is applied to a group of drugs used to treat
psychosis. Common conditions with which antipsychotics might be used include schizophrenia, mania and delusional
disorder.
Terminology
Antipsychotics are also referred to as neuroleptic drugs, or simply neuroleptics. The word neuroleptic is
derived from Greek; neuro refers to the nerves and
lept means "to take hold of". Thus the word means "taking hold of one's nerves". This term reflected the fact that the
drugs commonly made movement more difficult and sluggish, which clinicians 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.
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. Some antipsychotics (haloperidol, pimozide) are used off-label to treat Tourette 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 supposedly 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.
Common antipsychotic drugs
Commonly used antipsychotic medications are listed below by drug group. Trade names appear in parentheses.
-
- 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 mg 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's 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 equally high doses every 12
hours (75-400mg 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 who 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. Currently, 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:
- Aripiprazole (Abilify) - Dosing 5 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.[citation needed]
- Under clinical development - Bifeprunox; norclozapine
(ACP-104).
- 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 isn't generally 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 that 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. [1]
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 which 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.[2]
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 which 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 typically 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.
[citation needed]
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 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,[3] 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 particularly, 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, while 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.[4][5] 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.[6]
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.[7][8] 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.[9] Evidence from comparison studies indicates that at least some individuals recover
from psychosis without taking antipsychotics, and may do better than those who do take antipsychotics.[10] Some argue that, overall, the evidence suggests that antipsychotics only help if
they used selectively and are gradually withdrawn as soon as possible.[11]
A dose response effect has been found in one study from 1971 between increasing neuroleptic dose and increasing number of
psychotic breaks.[12][verification needed]
Typical vs Atypical comparison
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.[13] 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.[14] This phase consisted on a second randomization of the patients who 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. [15] 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.
See also
References
- ^ 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.
- ^ BBC NEWS, Schizophrenia trials 'promising'
- ^ Photos and videos of tardive dyskinesia can be seen here.
- ^ American Psychiatric Association (2004) Practice Guideline for the
Treatment of Patients With Schizophrenia. Second Edition.
- ^ 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.
- ^ 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
- ^ 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.
- ^ 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
- ^ Moncrieff J. (2006) Does antipsychotic withdrawal provoke psychosis? Review
of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr
Scand. Jul;114(1):3-13. PMID 16774655
- ^ 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
- ^ 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
- ^ Prien R, Levine J, Switalski R (1971).
"Discontinuation of chemotherapy for chronic schizophrenics". Hosp Community Psychiatry 22 (1): 4-7. PMID
4992967.
- ^ Lieberman J et al (2005). "Effectiveness of antipsychotic
drugs in patients with chronic schizophrenia". N Engl J Med 353 (12): 1209-23. PMID
16172203.
- ^ 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. PMID 16585435.
- ^ McEvoy J et al (2006). "Effectiveness of
clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who 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.
External links
|
Psycholeptics: antipsychotics (N05A) |
| Phenothiazine typical antipsychotics |
Chlorpromazine •
Fluphenazine • Mesoridazine • Perphenazine • Prochlorperazine • Promazine • Thioridazine/Sulforidazine • Trifluoperazine |
| Other typical antipsychotics |
Indoles
(Molindone) • Butyrophenones (Azaperone, Benperidol, Droperidol,
Haloperidol) • Thioxanthenes (Flupentixol, Chlorprothixene, Thiothixene, Zuclopenthixol) • diphenylbutylpiperidines
(Fluspirilene, Penfluridol, Pimozide) • other (Loxapine) |
| Atypical antipsychotics |
Butyrophenones
(Melperone) • Indoles (Sertindole, Ziprasidone) • Benzamides
(Sulpiride, Remoxipride, Amisulpride) • diazepines/oxazepines/thiazepines (Clozapine,
Olanzapine, Quetiapine) • other (Aripiprazole, Risperidone, Paliperidone, Zotepine) |
This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)
