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Psychopharmacology: Underuse of Evidence-Based Treatments in Psychiatry
Mohamed Fayek, M.D.; Calvin Flowers, M.D.; Darin Signorelli, M.D.; George Simpson, M.D.
Psychiatric Services 2003; doi: 10.1176/appi.ps.54.11.1453

In the Psychopharmacology column in the August 2003 issue, we discussed treatments in psychiatry for which there is good evidence of superior efficacy but that are underused in today's practice (1). Here, we discuss three additional examples of underused proven treatments—electroconvulsive therapy (ECT), depot antipsychotic medications, and clozapine.

It would be hard to find a psychiatrist treating major mental illnesses who does not agree that ECT is the best treatment for seriously depressed patients, particularly those with psychotic symptoms, suicidal ideation, or comorbid medical illness. Catatonia and some cases of schizophrenia appear to respond to ECT, as does mania. However, the data are most impressive for depression. A recent review that included studies comparing sham ECT with a range of different ECT strategies showed that ECT is significantly superior to sham ECT; among patients who received ECT, the mean pre-post difference on the Hamilton Depression Rating Scale was 9.7 points (2).

The same authors reviewed reports of 18 trials that compared ECT with pharmacotherapy (2). Some of these studies could be criticized. For example, none included a tricyclic antidepressant dosage greater than 150 mg a day, and some treatments lasted for only three weeks. Different electrode placements were used for ECT, and in some studies placement was unilateral. Four of these trials included patients who had already failed a trial of pharmacologic treatment. Despite these limitations, ECT was significantly more effective than pharmacotherapy, and the dropout rate was significantly lower in the ECT group than in the pharmacotherapy group.

In a recent consensus statement, bilateral ECT was reported to be the most effective treatment for psychotic depression, which affects as much as .6 percent of the general population (3). Clinical experience, a range of controlled studies, and consensus statements concur that ECT works well for patients who have difficult-to-treat depression and that it leads to better outcomes than pharmacotherapy in controlled trials (3). It is therefore disturbing to see patients who have undergone multiple trials of antidepressants and have never received ECT.

ECT is now widely used in private-sector psychiatry, where the usefulness of this treatment is underscored by the fact that private insurers are willing to pay for it. Even though ECT was once widely used in public-sector psychiatry—and perhaps overused—it is particularly underused in the public sector now. We know of many public-sector training hospitals that do not perform ECT and must send their residents to other institutions or private hospitals to observe this procedure. Indeed, the four academic centers in the Los Angeles area that serve patients in the public sector, which are responsible for the care of at least 3,000 hospitalized patients each year, treated fewer than a dozen patients last year with ECT.

In the Psychopharmacology column in the May 2003 issue, Velligan and colleagues (4) presented evidence of very poor adherence to atypical antipsychotic regimens among 68 patients in Texas. Nonadherence is a complex issue, and many factors play a role, including the patient-therapist relationship, psychoeducation, and side effects of the medication. Plain forgetfulness is also a factor—many patients appear willing to take oral medication but simply forget to.

Early studies of medication adherence in the United Kingdom showed that no one can predict with certainty which patients will or will not take medication as prescribed. As a result, Johnson (5) suggested that depot medication should be the standard of care for maintenance treatment of all patients with schizophrenia. Controlled trials in the United States confirmed that adherence rates were better among patients who received depot medication than among those whose medication was administered orally and that the rates of side effects were similar in both groups (6). A meta-analysis subsequently conducted by Adams and colleagues (7) found greater global improvement among patients given depot antipsychotics than among those given oral antipsychotics and found similar rates of side effects in the two groups.

Despite evidence of the effectiveness of depot medications, the administration of these medications has not been widely adopted in the United States. In Europe and Australia, an estimated 40 percent of all patients with schizophrenia who are on maintenance treatment receive depot medication. The U.S. rate has never risen above 12 percent and is now around 1 percent of all prescriptions (8). The low rate may be related to exaggerated statements about the side effects of depot medications or to the expectation that the introduction of atypical antipsychotics would improve adherence. Concerns about tardive dyskinesia may also be a factor, particularly because of the evidence of a greater risk of tardive dyskinesia with conventional antipsychotics. Furthermore, many clinics do not have nurses to administer injections.

Previously we have noted that some patients actually prefer conventional antipsychotics (9). Therefore, if treatment is properly explained to patients and their treatment response is properly documented, depot medication is a very appropriate form of treatment for patients who do not adhere to medication regimens. The cost of noncompliance and associated relapse is high, yet this proven better treatment is all but ignored. Perhaps the advent of depot atypical agents will change this situation.

A study in the late 1980s by Kane and colleagues (10) established that clozapine is more effective than conventional antipsychotics for treatment-resistant schizophrenia, a finding that was subsequently confirmed by other studies (11,12). Although comparisons of clozapine and other atypical antipsychotics revealed less convincing differences, Marder and colleagues (13) have stated that "the clozapine data for treatment-resistant patients are stronger than those for other second-generation antipsychotics." Meta-analyses have supported this finding (14,15). Moreover, clozapine has been shown to reduce suicidal behavior (16) and aggressive behavior (17). Like other atypical antipsychotics, clozapine produces fewer extrapyramidal symptoms than conventional agents (18), which may increase its tolerability. Compared with conventional antipsychotics, clozapine and other atypicals are more effective in reducing negative symptoms—which may be related to the absence of extrapyramidal symptoms—and in some cases in reducing treatment-resistant positive symptoms.

The need for weekly and then fortnightly blood counts is a nuisance and perhaps a limitation in the use of clozapine, but on the other hand, chronic treatment-resistant schizophrenia is a serious illness, and the obvious advantages of clozapine would seem to far outweigh the risks. Nonetheless, although the sales of all other second-generation antipsychotics have skyrocketed, the use of clozapine has been on a flat trajectory Thus, despite evidence supporting the superiority of this treatment, it is not widely used. High dosages of atypical agents and various unproven combinations of conventional agents, atypicals, and mood stabilizers—or both approaches in combination—are used at enormous cost. Such practices are not confined to the United States. A recent study published in the British Journal of Psychiatry found up to a 16-fold difference in the rates of clozapine use in different regions of the city of Manchester, despite data from the United Kingdom showing that use of clozapine leads to an overall resource saving of £7,000 a year ($11,000 U.S.) (19).

Solutions to this costly problem, as with all the underused treatments described in this column, must involve education. No psychiatric trainee should graduate without experience in the use of clozapine, depot antipsychotics, and ECT. Community clinics should send psychiatrists for training in the indications for and use of these treatments, and rates of use should be monitored to determine whether the training has been effective. A common feature of all these treatments is that they are not routine or are more complicated to deliver than other treatments, thus requiring reorganization of practice resources, such as increasing the availability of trained nursing staff and obtaining access to a laboratory for routine blood monitoring. However, each of these treatments has documented benefits for patients who have treatment-resistant illness or difficulty adhering to treatment regimens. Therefore, organizational and educational efforts to promote use of these treatments would be well justified by the potential positive impacts on the quality of patient care, adherence, treatment outcomes, and costs.

The authors are affiliated with the Keck School of Medicine of the University of Southern California. Send correspondence to Dr. Simpson, who is editor of this column, at the Outpatient Psychiatric Clinic, University of Southern California Medical Center, 2020 Zonal Avenue, IRD 202, Los Angeles, California 90033 (e-mail, gsimpson@usc.edu).

Dwight-Johnson M, Lagomasino IT, Simpson GM, et al: Underuse of evidence-based pharmacotherapies for affective disorders. Psychiatric Services 54:1076—1078,  2003
[PubMed]
[CrossRef]
 
The UK ECT Review Group: Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 361:799—808,  2003
[PubMed]
[CrossRef]
 
Finlay-Jones R, Parker G: A consensus conference on psychotic depression. Australian and New Zealand Journal of Psychiatry 27:581—589,  1993
[PubMed]
[CrossRef]
 
Velligan DI, Lam F, Ereshefsky L, et al: Perspectives on medications adherence and atypical antipsychotic medications. Psychiatric Services 54:665—667,  2003
[PubMed]
[CrossRef]
 
Johnson DAW: The duration of maintenance therapy in chronic schizophrenia. Acta Psychiatrica Scandinavica 53:298—301,  1976
[PubMed]
[CrossRef]
 
Hogarty GE, Schooler NR, Ulrich R, et al: Fluphenazine and social therapy in the aftercare of schizophrenic patients: relapse analysis of a controlled study of fluphenazine decanoate and fluphenazine hydrochloride. Archives of General Psychiatry 36:1283—1294,  1979
[PubMed]
 
Adams CE, Fenton MK, Quraishi S, et al: Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. British Journal of Psychiatry 179:290—299,  2001
[PubMed]
[CrossRef]
 
National Prescription Audit Database: Retail and Provider Perspective. Fairfield, Conn, IMS Health, 2002
 
Abulseoud O, Fayek M, Kingsbury SJ, et al: Patients' preference for conventional antipsychotic medications. Psychiatric Services 53:537—538, 547,  2002
[PubMed]
[CrossRef]
 
Kane J, Honigfeld G, Singer J, et al: Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Archives of General psychiatry 45:789—796,  1988
[PubMed]
 
Rosenheck R, Cramer J, Xu W, et al: A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. New England Journal of Medicine 337:809—815,  1997
[PubMed]
[CrossRef]
 
Essock SM, Hargreaves WA, Covell NH, et al: Clozapine's effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacology Bulletin 32:683—697,  1996
[PubMed]
 
Marder SR: Evidence-based treatment for schizophrenia: a selected review. Contemporary Psychiatry, Dec 2002, pp 1—6
 
Geddes J, Freemantle N, Harrison P, et al: Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. British Medical Journal 321:1371—1376,  2000
[PubMed]
[CrossRef]
 
Davis JM, Chen N, Glick ID: A meta-analysis of the efficacy of second-generation antipsychotics. Archives of General Psychiatry 60:553—564,  2003
[PubMed]
[CrossRef]
 
Meltzer HY, Alphs L, Green AI, et al: Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial. Archives of General Psychiatry 60:82—91,  2003
[PubMed]
[CrossRef]
 
Citrome L, Volavka J, Czobor P, et al: Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatric Services 52:1510—1514,  2001
[PubMed]
[CrossRef]
 
Simpson GM, Varga E: Clozapine: a new antipsychotic agent. Current Therapeutic Research, Clinical and Experimental 16:679—686,  1974
[PubMed]
 
Hayhurst KP, Brown P, Lewis SW, et al: Postcode prescribing for schizophrenia. British Journal of Psychiatry 182:281—283,  2003
[PubMed]
[CrossRef]
 
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References

Dwight-Johnson M, Lagomasino IT, Simpson GM, et al: Underuse of evidence-based pharmacotherapies for affective disorders. Psychiatric Services 54:1076—1078,  2003
[PubMed]
[CrossRef]
 
The UK ECT Review Group: Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 361:799—808,  2003
[PubMed]
[CrossRef]
 
Finlay-Jones R, Parker G: A consensus conference on psychotic depression. Australian and New Zealand Journal of Psychiatry 27:581—589,  1993
[PubMed]
[CrossRef]
 
Velligan DI, Lam F, Ereshefsky L, et al: Perspectives on medications adherence and atypical antipsychotic medications. Psychiatric Services 54:665—667,  2003
[PubMed]
[CrossRef]
 
Johnson DAW: The duration of maintenance therapy in chronic schizophrenia. Acta Psychiatrica Scandinavica 53:298—301,  1976
[PubMed]
[CrossRef]
 
Hogarty GE, Schooler NR, Ulrich R, et al: Fluphenazine and social therapy in the aftercare of schizophrenic patients: relapse analysis of a controlled study of fluphenazine decanoate and fluphenazine hydrochloride. Archives of General Psychiatry 36:1283—1294,  1979
[PubMed]
 
Adams CE, Fenton MK, Quraishi S, et al: Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. British Journal of Psychiatry 179:290—299,  2001
[PubMed]
[CrossRef]
 
National Prescription Audit Database: Retail and Provider Perspective. Fairfield, Conn, IMS Health, 2002
 
Abulseoud O, Fayek M, Kingsbury SJ, et al: Patients' preference for conventional antipsychotic medications. Psychiatric Services 53:537—538, 547,  2002
[PubMed]
[CrossRef]
 
Kane J, Honigfeld G, Singer J, et al: Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Archives of General psychiatry 45:789—796,  1988
[PubMed]
 
Rosenheck R, Cramer J, Xu W, et al: A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. New England Journal of Medicine 337:809—815,  1997
[PubMed]
[CrossRef]
 
Essock SM, Hargreaves WA, Covell NH, et al: Clozapine's effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacology Bulletin 32:683—697,  1996
[PubMed]
 
Marder SR: Evidence-based treatment for schizophrenia: a selected review. Contemporary Psychiatry, Dec 2002, pp 1—6
 
Geddes J, Freemantle N, Harrison P, et al: Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. British Medical Journal 321:1371—1376,  2000
[PubMed]
[CrossRef]
 
Davis JM, Chen N, Glick ID: A meta-analysis of the efficacy of second-generation antipsychotics. Archives of General Psychiatry 60:553—564,  2003
[PubMed]
[CrossRef]
 
Meltzer HY, Alphs L, Green AI, et al: Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial. Archives of General Psychiatry 60:82—91,  2003
[PubMed]
[CrossRef]
 
Citrome L, Volavka J, Czobor P, et al: Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatric Services 52:1510—1514,  2001
[PubMed]
[CrossRef]
 
Simpson GM, Varga E: Clozapine: a new antipsychotic agent. Current Therapeutic Research, Clinical and Experimental 16:679—686,  1974
[PubMed]
 
Hayhurst KP, Brown P, Lewis SW, et al: Postcode prescribing for schizophrenia. British Journal of Psychiatry 182:281—283,  2003
[PubMed]
[CrossRef]
 
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