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Antipsychotics

Drugs & Medication

Antipsychotics

Atypical antipsychotics | Phenothiazines | Tardive dyskinesia | Typical antipsychotics | Lithium pharmacology

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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, although antipsychotics might be used to counter psychosis associated with a wide range of other diagnoses. Antipsychotics also have some effects as mood stabilizers, leading to their frequent use in treating mood disorder (particularly bipolar disorder) even when no signs of psychosis are present. Some antipsychotics (haloperidol, pimozide) are used off-label to treat Tourette syndrome.

Antipsychotics are also referred to as neuroleptic drugs, or simply neuroleptics. The word neuroleptic is derieved from Greek. 'Neuro' refers to the nerves and 'lept' means 'to take hold of'. Thus the word means 'taking hold of one's nerves' which implies their role in mood stabilization.

There are currently two main types of antipsychotics in use, the typical antipsychotics and atypical antipsychotics. A new class of antipsychotic drugs has recently been discovered, known as dopamine partial agonists. Clinical development has progressed rapidly on partial dopamine agonists, and one drug in this class (aripiprazole) has already been approved by the Food and Drug Administration. Although the underlying mechanism of this new class is different from all previous typical and atypical antipsychotics, dopamine partial agonists are often categorized as atypicals.

Typical antipsychotics are sometimes referred to as major tranquilizers, due to the fact that some of them can tranquilize and sedate. This term is increasingly disused because many newer antipsychotics do not have strong sedating properties and the terminology implies a connection with benzodiazepines, whereas none exists.

Contents

Common antipsychotic drugs

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

  • Typical antipsychotics:
    • Phenothiazines:
      • Chlorpromazine (Thorazine®)
        Fluphenazine (Prolixin®) - Available in decanoate (long acting) form
        Perphenazine (Trilafon®)
        Prochlorperazine (Compazine®)
        Thioridazine (Mellaril®)
        Trifluoperazine (Stelazine®)
  • Butyrophenones
    • Haloperidol (Haldol®) - Available in decanoate (long acting) form
    • Droperidol
      Pimozide (Orap®) - Used to treat Tourette syndrome
  • Atypical antipsychotics:
    • Clozapine (Clozaril®) - Requires weekly to biweekly CBC (FBC) due to risk of agranulocytosis (a severe decrease of white blood cells).
    • Olanzapine (Zyprexa®) - Used to treat psychotic disorders including 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)
    • 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.
  • Dopamine partial agonists:
    • Aripiprazole (Abilify®) - Among the newest (2006) atypical antipsychotics; 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.
    • 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.

The most common antipsychotic drugs are now off-patent, meaning any pharmaceutical company is legally allowed to produce cheap generic versions of these medications. Whilst this makes them a great deal cheaper than the atypical drugs which are still being manufactured under patent constraints, atypical drugs are preferred as a first line treatment due to the fact that 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 and effectiveness

All antipsychotic drugs tend to block the D2 receptors in the dopamine pathways in the brain, so the normal effect of dopamine release in the relevant synapses is reduced.

It is the blockade of D2 receptors in the mesolimbic pathway of the brain which is thought to produce the intended antipsychotic effect.

Typical antipsychotics are not particularly selective and also block the same 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).

Atypical antipsychotic drugs have a similar blocking effect on D2 receptors but seem to be a little more selective, targeting the intended pathway to a larger degree than the others. They also block or partially block serotonin receptors (particularly 5HT2A,C and 5HT1A receptors).

This combination of effects on both dopamine and serotonin receptors might be why atypical antipsychotic drugs tend to have fewer side effects than typicals and have a seemingly additional effect on the 'negative symptoms' of schizophrenia.

Anti-psychotics can be classified on a spectrum of low potency to high potency, where potency refers 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, which have dosages of several hundred milligrams.

Some people who become psychotic do not seem to respond to antipsychotic medication, despite studies showing that the drug is blocking the same number of receptors as in other people who do respond to the treatment.

Side effects

The range of interactions can produce different adverse effects including extrapyramidal reactions, including 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, not infrequently, 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. (Photos and video can be seen here). 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.

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, meaning that it just makes the patient feel bad. This side-effect is a major problem for patients with schizophrenia in that it causes them to discontinue medication, and this produces a relapse of psychotic symptoms.

Whilst this may seem a daunting list, it must be noted that many people suffer few of the obvious side effects from taking antipsychotic medication. Some side effects, such as subtle cognitive problems, foot rocking, or drooling, in the case of akinesia go unnoticed.

Other symptoms of akinesia of antipsychotics include deterioration of teeth due to a lack of saliva. These symptoms are hard to spot and are often dismissed.

Typical vs Atypical comparison

While the atypical, second-generation medications were marketed as offering greater efficacity 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 [1]. 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 glycose, 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 it should be noted that 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 [2]. 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 [3]. 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.

History and design

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.

See also

References

External links


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This guide is licensed under the GNU Free Documentation License. It uses material from the Wikipedia.


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