ANTIPSYCHOTIC DRUGS & AUTISM

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, autism spectrum disorders and delusional disorder.

research on anti-psychotics

Although no medication acts a 'cure' for Autism Spectrum Disorders, typical and atypical anti-psychotics have proved to be the most effective medication for reducing the overall symptoms to date. Their use in not wide spread due to side-effects, particularly with long-term use.

Typical anti-psychotics such as haloperidol, fluphenazine, and thioridazine, were actually developed to treat schizophrenia. They help to manage symptoms of Autism Spectrum Disorders but possible side effects include stiffness, restlessness and involuntary movements. Long-term use can result in permanent tardive dyskinesia (Sikich 2001).

Research has focused on atypical antipsychotics, especially risperidone, which has the largest amount of evidence that consistently shows improvements in irritability, self-injury, aggression, and tantrums associated with ASD. In the United States, risperidone is approved for treating symptomatic irritability in autistic children and adolescents aged 5–16 years. In short-term trials (up to 6 months) most adverse events were mild to moderate, with weight gain, drowsiness, and high blood sugar requiring monitoring. Its long term efficacy and safety have not been fully determined. It is unclear whether risperidone improves autism's core social and communication deficits. As with most interventions for Autism Spectrum Disorders, much more research is needed to accurately establish these medications as evidence-based treatments.

Terminology of antipsychotics

Antipsychotics are also referred to as neuroleptic drugs, neuroleptics. The word neuroleptic is derived from Greek, 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 of antipsychotics

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; while 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 of antipsychotics

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. 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.

Atypical 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 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.[1]
* 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. [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 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.

Drug action of antipsychotics

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.[4]

Side effects of antipsychotics

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,[5] 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 of antipsychotics for mental disorders

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.[6][7] 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.[8]

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.[9][10] 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.[11] 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.[12] Some argue that, overall, the evidence suggests that antipsychotics only help if they used selectively and are gradually withdrawn as soon as possible.[13]

A dose response effect has been found in one study from 1971 between increasing neuroleptic dose and increasing number of psychotic breaks.[14]

Typical versus atypical antipsychotics

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.[15] 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.[16] 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. [17] 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.

basic principles for medication as an Autism intervention

If you decide to allow medication for your child, it can pay to not tell others. For example, a teacher may notice an improvement in behavior without being influenced by knowledge of the medication being used. Other interventions should not be changed at this time, so that you can tell if changes are due to the medication.

Medications should be introduced carefully, as the nervous system in many people with Autism is very sensitive and only a low dose of medication may be needed. Medication trials should always start with the lowest possible dose, with gradual increases until its effectiveness is established. The timing of medication is very important so parents must have a clear understanding of when it should be taken.

It can be useful to keep a diary of your child's response to medication, especially if several medications are prescribed. Don't stop medications abruptly, particularly if they have been taken for a long time. Always check with your doctor on the best way to discontinue a prescribed medication if its benefits do not outweigh its risks.

A 'baseline' should be set before using medication. These means getting an accurate idea of symptoms so that you can assess how well the medication is working e.g. how often is the child having seizures, or violent outbursts, or how many hours sleep each night. Where possible, this should be written down before, during, and after using a medication trial.

A child with Autism or Asperger's syndrome may not respond in the same way to medications as other children. Ideally parents should work with a doctor who has experience with Autism Spectrum Disorders.

Learn about the possible side effects of the medication and monitor your child closely for their signs.

autistic adults and medication

Many autistic adults themselves are against the over prescription of neuroleptic drugs in autistic people to control behavior. Others with co-morbid disorders have been relieved to have medication to manage these problems. Some psychiatrists are just now beginning to explore minimal doses of medication for autistic children. People against the use of Neuroleptic medications for people with Autism have formed an organization called Autistic People Against Neuroleptic Abuse.

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. Retrieved on 2007-11-08.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. ^ BBC NEWS, Schizophrenia trials 'promising'
4. ^ 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. Retrieved on 2007-11-08.PMID 16930948
5. ^ Photos and videos of tardive dyskinesia can be seen here.
6. ^ American Psychiatric Association (2004) Practice Guideline for the Treatment of Patients With Schizophrenia. Second Edition.
7. ^ 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.
8. ^ 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
9. ^ 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.
10. ^ 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
11. ^ 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
12. ^ 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
13. ^ 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
14. ^ Prien R, Levine J, Switalski R (1971). "Discontinuation of chemotherapy for chronic schizophrenics". Hosp Community Psychiatry 22 (1): 4-7. PMID 4992967.
15. ^ Lieberman J et al (2005). "Effectiveness of antipsychotic drugs in patients with chronic schizophrenia". N Engl J Med 353 (12): 1209-23. PMID 16172203.
16. ^ 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.
17. ^ 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.

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