Antipsychotic drugs

Definition

Antipsychotic drugs, sometimes called major tranquilizers or neuroleptics are drugs which are effective in treatment of schizophrenia, although most have additional indications.

Description

The anti-psychotics are a diverse group of drugs which are effective in control of schizophrenia, but that can have a large number of other uses. While these drugs can be referred to in terms of “generations”, the usual way of grouping them is as conventional and atypical. The conventional drugs are derived from the antihistamines , and have many of the same side effects, so that some drugs find uses other than treatment of schizophrenia. For example, prochlorperazine is an effective antipsychotic agent, and chemically belongs in this class, but is used almost exclusively for control of nausea and vomiting. Promethazine has been used as an antipsychotic, but its current use is in cough remedies and treatment of the symptoms of cold and allergies . The fact that these drugs, while closely related chemically, have such diversity of actions indicates that all the drugs in this group will have a large number of unwanted side effects. The drugs in this group are categorized as high, intermediate and low potency. The low potency drugs are less specific and so tend to have a larger number of side effects. Drug selection is based on individual patient response to the drug, and observed side effects, but another factor can be the route of administration. Some of these drugs are available in rectal suppositories, oral liquids, or long acting injections. These routes of administration can make it easier to administer the drug, and easier for a caregiver to be assured that the patient is taking the medication. Recent evidence suggests that genetics might play a role in severity and treatment response in schizophrenia, and this might modify drug selection in the future.

Chlorpromazine is the prototype drug for this class, and while it has largely been supplanted by newer drugs, it has a wide range of additional uses, including treatment of hiccups that have not responded to other treatments, treatment of acute intermittent porphyria, and for treatment of tetanus.

Thioridazine has very significant adverse effects (see precautions and should only be used for patients who have been unresponsive to other drugs, or WHO ARE unable to take the other drugs because of severe untoward effects.

Trifluperazine, fluophenazine and perphenazine are closely related drugs in the intermediate to high potency range. Fluophenazine has the advantage of being available in two long-acting injectable forms. These long acting injections assure steady blood levels without the peaks and valleys associated with oral dosing, and also provide assurance that the patient is getting all required doses.

Loxapine has a high affinity for the proteins known as dopamine and serotonin receptors, and CAN show a different pattern of response and side effects than other drugs in this group.

Molindone: a careful review of the literature on molindone found that it was comparable to other drugs in this group in terms of side effects and effectiveness, but does cause significantly more weight loss .

Thiothixene: no unique properties. In one study, it was found that it took two weeks from the start of treatment with chlorpromazine or thiothixene to show any benefit, compared with 2-6 days for the newer compounds.

Haloperidol has been used particularly for control of aggressive behavior in children. It has also been effective for the control of tics and vocal utterances in Tourette disorder.

The atypical antipsychotics are atypical only in the sense that they are chemically unrelated to the older drugs, and are now commonly called second generation antipsychotics. A number of claims have been made for these drugs, not all of which haven been confirmed; however, they do appear to have a different side effect profile, and in some cases are effective in patients who are not responsive to the older drugs, although this benefit has only been demonstrated for clozapine. These drugs tend to be similar to each other in effectiveness and choice is generally made based on availability of an appropriate dosage form and the side effect profile. Because clozapine has potentially severe adverse effects, it should be reserved for patients who have failed trials of other drugs.

Clozapine is the oldest drug in the group, and the only one which has been demonstrated to be effective in resistant cases. Because of risk of severe adverse effects, and the need for regular monitoring, it is reserved for patients who have failed to respond to other second generation antipsychotics. Because of the potential severity of the adverse effects, patients receiving clozapine must be registered with the manufacturer, and both the prescribing physician and dispensing pharmacist must sign documentation of blood tests before the medication can be dispensed.

Risperidone is the only second generation antipsychotic with a long-acting injectable dosage form. In one study it was found to be slightly more effective at resolving the sexual dysfunction associated with schizophrenia than other drugs tested, although the results were not conclusive.

Olanzapine is more sedating than other drugs in the group, and can be useful for patients with agitation and insomnia .

Quetiapine has no anticholinergic effect—does not cause dry mouth or related side effects.

Ziprasidone might have some antidepressant effects. Because of a short half-life, ziprasidone requires twice daily dosing.

Aripiperazole might be less likely to cause weight gain than other drugs in this class.

Recommended dosage

See product specific references

Precautions

Drugs in this class have many warnings. The following are taken from the manufacturer&s package insert and represent only the most serious hazards. See product specific information for full details.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary movements, can develop in patients treated with neuroleptic (antipsychotic) drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, there is no way to predict which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Given the likelihood that some patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Occasionally, these drugs can mask the signs and symptoms of the tardive dyskinesia they have caused. whether this symptom suppression has a long-term effect om the course of tardive dyskinesia is unknown. Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to neuroleptic drugs, and, for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients require treatment despite the presence of the syndrome. Tardive dyskinesia is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of the tongue, puffing of the cheeks, puckering of the mouth, chewing movements). Sometimes these are accompanied by movements of extremities, and, in rare cases, these involuntary movements of the extremities are the only manifestations of tardive dyskinesia.

QUESTIONS TO ASK YOUR PHARMACIST

• What are the likely adverse effects I will experience taking this medication?
• What are the possible interactions with my other prescription and over-the-counter medications?

Neuroleptic malignant syndrome (NMS): A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are high fever, muscle rigidity, and altered mental status. NMS can also cause an irregular pulse or blood pressure , rapid pulse, sweatiness, and heart rhythm abnormalities. The evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to consider other possible causes of these symptome: pneumonia , serious infection, heat stroke , drug fever, or brain disorders.

The management of NMS should include the following:

• Immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy.
• Intensive symptomatic treatment and medical monitoring.
• Treatment of any other serious medical problems for which specific treatments are available.

There is no general agreement about specific drug treatment for uncomplicated NMS. If a patient still requires antipsychotic drug treatment after recovering from NMS, the potential reintroduction of a neuroleptic drug therapy should be very carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Atypical (second generation) antipsychotics: Increased mortality in elderly patients with dementia-related psychosis: Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared with placebo or dummy pills. Over the course of one 10-week controlled trial, the rate of death in patients taking neuroleptics was about 4.5%, compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Atypical antipsychotics are not approved for the treatment of patients with dementia-related psychosis.

Clozapine Agranulocytosis: Because of a significant risk of agranulocytosis, a potentially life-threatening reduction in the number of infection-fighting white blood cells, reserve clozapine use in 1) the treatment of severely ill patients with schizophrenia who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment, or 2) for reducing the risk of recurrent suicidal behavior. Patients being treated with clozapine must have a baseline white blood cell (WBC) before initiation of treatment, as well as regular WBC counts during treatment and for 4 weeks after discontinuation of treatment. Clozapine is available only through a distribution system that ensures monitoring of WBC counts according to the schedule described, prior to delivery of the next supply of medication.

Seizures: Seizures have been associated with the use of clozapine. Dose appears to be an important seizure predictor, with a greater likelihood at higher clozapine doses. Use caution when administering clozapine to patients with a history of seizures or other predisposing factors. Advise patients not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others.

Myocarditis : Clozapine has been associated with myocarditis, a potentionally fatal inflammation of the heart muscle, especially during the first month of therapy. In patients in whom myocarditis is suspected, discontinue clozapine treatment promptly.

Mesoridazine, thioridazine: Some antipsychotics have been shown to interfere with the electrical conduction within the heart, and can cause dangerous rapid rhythms and death. Because of their potential for significant, possibly life-threatening, rhythm problems, reserve use of these drugs for treatment of schizophrenic patients who fail to show an acceptable response to adequate courses of treatment with other antipsychotic drugs.

Side effects

There drugs have a large number and wide range of side effects. Consult drug specific references.

Among the first generation (conventional) anti-psychotics, anti-cholinergic effects are common. These include dry mouth, decreased sweating, constipation and dry eyes. Somnolence and low blood pressure are common.

KEY TERMS

Agranulocytosis —An acute condition marked by high fever and a sharp drop in the number of some types of white blood cells.

Anticholinergic —A drug that blocks the action of acetylcholine, causing many effects including but not limited to reductions in secretions such as tears and saliva, as well as reduction in the movement of the intestines, causing constipation.

Antihistamine —A drug that blocks the action of histamine, used to treat allergies, nasal congestion, rashes and other problems.

Diaphoresis —Perspiration, particularly heavy perspiration caused by drugs or other artificial means.

Neuroleptic —Synonym for antipsychotic, a major tranquilizer.

Schizophrenia —Any one of several psychiatric disorders marked by distortions of reality, thought disturbances, and withdrawal from social contact.

Seizure —A sudden attack caused by abnormal electrical discharges from the brain.

Tachycardia —Rapid heart beat.

Weight gain is common with most drugs in this class, and may be dramatic at the start of treatment. In one comparison, the weight gain was greatest with the second generation drugs olanzapine and risperidone, and somewhat less severe but still significant with haloperidol, a first generation agent. Food cravings and binge eating have been reported in patients treated with clozapine and olanzapine, and this combined with metabolic alterations might explain the weight gain. Administration of metformin, an insulin sensitizer used in treatment of diabetes, can be helpful in controlling the weight gain associated with the antipsychotic drugs.

Interactions

These drugs can cause a large number of interactions. Consult drug specific references.

Caregiver concerns

Be aware that the conventional antipsychotics may have a delayed onset of action, although the side effects may be observed at the start of treatment,

Be familiar with symptoms of severe adverse effects, including neuroleptic malignant syndrome and tardive dyskinesia.

Observe patient carefully for adherence to medication regimen.

Resources

BOOKS

Meyer, J, Quenzer, L. Psychopharmacology: Drugs, the Brain, and Behavior. Sunerland, MA: Sinauer Associates, 2005.

Reynild, J (ed). Martindale the Extra Pharmacopoeia 30th ed. London: The Pharmaceutical Press, 1993.

PERIODICALS

Adams, CE, Rathbone, J, Thornley, B et al. “Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials.”BMC Med. (October 17, 2005) 3:15.

Bagnall, A, Fenton, M, Kleijnen, J, Lewis, R. “Molindone for schizophrenia and severe mental illness.”Cochrane Database Syst Rev. (January 24, 2007) (1): CD002083.

Baptista, T, Rangel, N, Fernández, V, et al. “Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial.”Schizophr Res. (July 2007) 93(1-3):99-108.

Campbell, DB, Ebert, PJ, Skelly, T et al. “Ethnic stratification of the association of RGS4 variants with antipsychotic treatment response in schizophrenia.”Biol Psychiatry. (January 1, 2008) 63(1):32–41.

Conley, RR, Kelly, DL, Nelson, MW et al. “Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia.”Clin Neuropharmacol. (Jul-Aug 2005) 28(4):163-8.

Dossenbach, M, Treuer, T, Kryzhanovskaya, L et al. “Olanzapine versus chlorpromazine in the treatment of schizophrenia: a pooled analysis of four 6-week, randomized, open-label studies in the Middle East and North Africa.”J Clin Psychopharmacol. (August 2007) 27(4):329-37.

Gray, R, Leese, M, Bindman, J et al. “Adherence therapy for people with schizophrenia. European multicentre randomised controlled trial.”Br J Psychiatry. (December 2006) 189:508-14.

Kelly, DL, Conley, RR. “A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia.”Psychoneuroendocrinology. (April 2006) 31(3):340-6.

Kluge, M, Schuld, A, Himmerich, H, et al. “Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study.”J Clin Psychopharmacol. (December 2007) 27(6):662-6.

Perez-Iglesias, R, Crespo-Facorro, B, Amado, JA, et al. “A 12-week randomized clinical trial to evaluate metabolic changes in drug-naive, first-episode psychosis patients treated with haloperidol, olanzapine, or risperidone.”J Clin Psychiatry. (November 2007) 68(11):1733-40.

Rosenheck, RA, Leslie, DL, Sindelar, J. “Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia.”Am J Psychiatry. (December 2006) 163(12):2080-9.

Tohen, M, Jacobs, TG, Feldman, PD. “Onset of action of antipsychotics in the treatment of mania.”Bipolar Disord. (September 2000) 2(3 Pt 2):261-8.

OTHER

http://www.pbs.org/wgbh/aso/databank/entries/dh52dr.html

http://www.nlm.nih.gov/medlineplus/schizophrenia.html

http://www.nimh.nih.gov/health/publications/medications/complete-publication.shtml

http://www.medscape.com/http://online.factsandcomparisons.com/

http://www.clozapineregistry.com/http://www.risperdal.com/risperdal/

http://zyprexa.com/about_zyprexa.jsp?WT.mc_id=ZypCSBip0001&WT.srch=1

http://www.ziprasidone.com/http://www.abilify.com/abilify/home/index.jsp?BV_UseBVCookie=Yes

http://www.schizophrenia.com/

ORGANIZATIONS

National Alliance for Research on Schizophrenia and Depression (NARSAD), 60 Cutter Mill Road, Suite 404, Great Neck, NY, 11021, (516) 829-0091, (800) 829-8289, (516) 487-6930, [email protected], http://www.NARSAD.org.

Sam Uretsky PharmD