Recommendations:

The first line recommendation is to try one of the four new generation, "atypical" antipsychotics. From here, you will be able to access information about how and when to prescribe these medications.

A number of pathways in the algorithm could have brought you to this recommendation to choose from among the newer antipsychotics. It could be that this is the first treatment with an antipsychotic, or this could be a patient with an unsatisfactory level of recovery or significant side effects on the most recent antipsychotic used. The evidence is that these newer drugs have a generally more favorable side effect profile compared with the older, standard neuroleptics, and in the cases of olanzapine and risperidone at least, slightly better efficacy on a number of symptom dimensions.¹ These agents are all clearly better in producing fewer secondary negative symptoms, and are strongly suspected to lower the risk for tardive dyskinesia when used at doses that do not produce manifest parkinsonian side effects. Compliance and patient satisfaction are likely to be better.

Although there may be some controversy about first-line usage of these drugs due to the marked increased up-front costs compared to the older generic drugs, it should be noted that the federal Health Care Financing Administration (HCFA) has issued a strongly worded guidance letter to state Medicaid directors recommending that the new drugs be first-line for Medicaid patients with schizophrenia. (See Mental Health Weekly 1998:8(9):1-4) A similar recommendation was issued in a letter by Steven H. Hyman, M.D., former Director of the National Institute of Mental Health.

For a more detailed discussion of the evidence-basis for the preference of an atypical over a typical antipsychotic, click here.

The role of ziprasidone (Geodon) in this algorithm is still in the process of being evaluated to determine its proper place in all of the various "nodes" or decision-points.

For information on choosing, dosing, and switching atypicals, click here.

For information on which atypicals work most rapidly, click here.

Second-Line Choices

For first-onset patients, the standard, typical neuroleptics listed below would be second-line choices For best results, use them at doses no higher than those required to produce minimal Parkinsonian side effects. (4) Click here to go through the algorithm for evaluating the adequacy of trials of standard, typical neuroleptics.

• chlorpromazine (Thorazine)
• fluphenazine (Prolixin HCl)
• haloperidol (Haldol)
• perphenazine (Trilafon)
• thiothixene (Navane)
• trifluoperazine (Stelazine)

Other second line choices, comparable in efficacy to the neuroleptics above, are some older antipsychotics and neuroleptics, all of which may be considered "somewhat atypical" at least in terms of side effects, and some of which may be preferable to use at the second-line level. Sometimes, one will return to considering certain of these drugs after adequate trials of or intolerance to the newer antipsychotics and standard, typical neuroleptics (above) and if clozapine is either refused, not tolerated, or ineffective:

• chlorprothixene (Taractan): a sedating thioxanthene derivative that is rarely used.
• loxapine (Loxitane): slight support for being a somewhat atypical neuroleptic that may occasionally have superior efficacy under some circumstances (5)
• mesoridazine (Serentil): slight support for being a somewhat atypical neuroleptic that may occasionally have slightly superior efficacy (6). A "boxed warning" was added to the package insert in September, 2000 advising that mesoridazine may prolong the QTc interval in a dose-related manner, and may be associated with torsade de pointes-type arrhythmias and sudden death. Therefore, it should only be used for patients who fail to show an acceptable response to other antipsychotics. It is contraindicated to combine it with other drugs that prolong the QTc. Baseline EKG and serum K levels should be drawn.
• molindone (Moban): Appears to have equal efficacy, at best, to standard neuroleptics but with a different side effect profile. (low parkinsonism, high akathisia, no weight gain and possible weight loss, among the least effect on seizure threshold)(7)
• pimozide (Orap): slight support for being a somewhat atypical neuroleptic that may occasionally have slightly superior efficacy for negative symptoms (8)
• thioridazine (Mellaril): Many large studies show that it has equal efficacy to the typical neuroleptics but has a different side effect profile. (low parkinsonism and akathisia, high sedation, postural hypotension, anticholinergic side effects, retrograde ejaculation) A "boxed warning" was added to the package insert in July, 2000 advising that thioridazine may prolong the QTc interval in a dose-related manner, and may be associated with torsade de pointes-type arrhythmias and sudden death. At a dose of 300 mg per day, the increase in the QTc was found to be about 36 milliseconds according to an FDA mandated study. Therefore, it should only be used for patients who fail to show an acceptable response to other antipsychotics. It is contraindicated to combine it with other drugs that prolong the QTc. It is also contraindicated with other drugs that could inhibit its cytochrome P450 metabolism such as fluoxetine, paroxetine, fluvoxamine, and also pindolol and propranolol. Baseline EKG and serum K levels should be drawn. See the package insert for full details.

If you are participating in Data Reporting, choose the appropriate Recommendation Number for reporting on the Data Reporting Form, and click on the Form box below to enter data:

First trial of a new generation (not clozapine) antipsychotic: Recommendation Number 13-1
Second: 13-2
Third: 13-3
Fourth: 13-4
Fifth: 13-5 (e.g. - aripiprazole, when available)

Evidence discussion regarding efficacy comparison of typical vs atypical antipsychotics

• Most major reviews of the pertinent evidence(9-14) have concluded that the new atypical antipsychotic medications are preferred for first-line use in treatment of initial episodes and exacerbations of schizophrenia. However, there are some dissenting opinions. The Royal College of Psychiatrists in Britain recently performed a metaanalysis of 52 randomized trials involving 12,649 patients.(15) They concluded that most of the apparent advantages in efficacy of the new-generation antipsychotics could be attributed to the use of excessive doses of conventional neuroleptics in the trials. They recommended that initial treatment of episodes of schizophrenia be with the lowest effective dose of a conventional neuroleptic. In their view, an atypical should be considered only if the conventional neuroleptic is poorly tolerated or if the response is unsatisfactory.
• One atypical in particular-quetiapine-has also been the subject of controversy. An evidence analysis by the Cochrane Group (updated 27 May 2000)(16,17) raised questions about the robustness of quetiapine's efficacy in schizophrenia. The Cochrane Group is well known for its high quality systematic reviews; they consider all published studies and also search extensively for unpublished data. This is done to reduce the problem of "publication bias," which occurs when an overview of the literature reaches a falsely positive impression of a treatment because negative data were never published.(18)
• The Cochrane Group reviewed 42 papers and reports on quetiapine, including 11 randomized controlled trials (most of very short duration). They found that drop-out rates were very high (36-64%)-and only marginally lower in the quetiapine groups than in the neuroleptic control groups. The authors concluded that interpreting the results of these studies was very difficult and that more studies with longer-term outcomes were needed "before quetiapine's use can be recommended."
• Adding to the concerns raised by the Cochrane Group, a recent small study of 23 stable schizophrenia patients switched from conventional neuroleptics or risperidone to open-label quetiapine(19) found that only five patients completed 77-96 weeks of treatment. The intention was to continue treatment for 3 years. Patients kept having breakthrough symptoms despite increasing dosage. When quetiapine was approved for marketing, the manufacturer discontinued the study. The authors speculated in their poster that a possible mechanism to explain these clinical findings could be quetiapine's weak dopamine-D2 receptor binding and its tendency to induce a proposed dopamine receptor supersensitivity.(20)
• In contrast to this experience, more-positive results with quetiapine were recently presented in another poster session.(21) The researchers described a multicenter open-label trial involving 751 outpatients with different psychotic diagnoses. Patients were started on either quetiapine or risperidone and maintained for 16 weeks. It is unclear whether they were acutely ill on entrance to the study or whether their illnesses were stable. Patients did improve on both treatments, and the drop-out rate appeared to be only about 15%. At the end of the study, the mean daily dose was 317 mg for quetiapine and 4.5 mg for risperidone. EPS were greater with risperidone.
• Cochrane Group analyses have been done on 20 published studies involving olanzapine(22) and on 14 studies of risperidone.(23) They conclude that these atypical antipsychotics are clearly efficacious, with perhaps marginally greater benefit and tolerability than haloperidol. The Cochrane Group has also already published commentary on the Royal College metaanalysis(15) of the trials of atypical antipsychotics.(24) They noted that the review did not pay sufficient attention to the higher drop-out rates on conventional neuroleptics, and that this inflated the impression of efficacy of the neuroleptics. In their opinion, the recommendations derived from the review "could harm people with schizophrenia."
• When all reviews, evidence, and opinions are combined, it appears reasonable to state that the atypicals, particularly risperidone and olanzapine, seem to offer somewhat improved efficacy and/or potential for a reduced side-effect burden. They may be the preferred antipsychotics in the short-term inpatient setting.