Note: Recovery and normalized activity are the goals of adequate antipsychotic trials. Response short of this should be considered unsatisfactory. Review diagnosis and psychosocial factors, and continue with the algorithm recommendations as indicated. Consult the "Levels of Recovery from Psychotic Disorders" chart to gauge the quality of your patient's improvement.
Click on a medication to see dosing recommendations:
Risperidone, Olanzapine, Quetiapine, Ziprasidone, Aripiprazole, Others..............How to Switch
Summary of Evidence regarding Side Effect Differences
(1)Osser DN, Najarian D, Dufresne RL. Olanzapine increases weight and triglycerides. Journal of Clinical Psychiatry 1999; 60:767-770; Meyer JM. Novel antipsychotics and severe hyperlipidemia. Journal of Clinical Psychopharmacology 2001;21:689-374
(2)Lindenmeyer J-P, Patel R. Olanzapine-induced ketoacidosis with diabetes mellitus. American Journal of Psychiatry 1999; 156:1471.
(3)Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. American Journal of Cardiology 1998; 81:18B-25B.
(4)Ereshefsky L. Pharmacologic and pharmacokinetic onsiderations in choosing an antipsychotic. Journal of Clinical Psychiatry 1999; 60:21.
(5)McManus DQ, Arvanitis LA, Kowalcyk MD, Group STS. Quetiapine, a novel antipsychotic: experience in elderly patients with psychotic disorders. Journal of Clinical Psychiatry 1999; 60:292-298.
(6)Madhusoodanan S, Suresh P, Brenner R, Pillai R. Experience with the atypical antipsychotics - risperidone and olanzapine in the elderly. Annals of Clinical Psychiatry 1999; 11:113-118.
(7)Glick ID, Fryburg D, O'Sullivan RL, et al. Ziprasidone's benefits versus olanzapine on weight and insulin resistance. American Psychiatric Association Annual Meeting New Research Poster Session 261. New Orleans, LA, May 8, 2001.
Further discussion of side effect comparisons.
Direct comparisons of risperidone and olanzapine have demonstrated several differences between the two drugs in side effects. Olanzapine produced greater weight gain in both the Janssen-sponsored 8-week comparison(1) and the Lilly 28-week study(2) (4.1 kg vs. 2.3 kg, p = 0.015, in the latter).(3) There was no difference in EPS between the two in the Janssen study, which had a mean risperidone dose of 4.8 mg, but more EPS were seen with risperidone in the Lilly study, which used 7.2 mg. The Lilly study(2) reported that prolactin elevation was more common at end-point with risperidone (90.3% vs. 36%; p < 0.001), but that elevated liver enzymes (p = 0.019) and depressed neutrophil counts (4.3% vs. 0.6%; p = 0.034) were more common with olanzapine. A recent open but randomized comparison presented in a poster session(4) (n = 41) showed a significantly greater incidence of sexual side effects with risperidone than with olanzapine (50% vs. 11%; p = 0.032), but these side effects did not correlate with prolactin levels. Another published report also found no association between presumably prolactin-mediated side effects and prolactin levels.(5)
In adolescents, there has been some suggestion of more-frequent initial intolerance to risperidone compared with olanzapine. Preliminary results of a double-blind comparison of olanzapine and risperidone (n = 23) showed that patients taking olanzapine remained on the medication significantly longer than did those taking risperidone (17 weeks and 8 weeks, respectively).(6)
In the five-dose quetiapine study(7) weight gain over 6 weeks ranged from 2 to 2.9 kg with the four efficacious doses. In the other large study(8) 25% of patients in the high-dose group gained greater than 7% of body weight, as compared to 5% on placebo. Quetiapine therefore appears to be intermediate between olanzapine and risperidone in inducing weight gain. Prolactin levels were lower than with placebo at all doses, but postural hypotension occurred in 12-14% of patients on daily doses over 300 mg (compared with 2% of patients taking haloperidol and 8% of those taking placebo).(7) In the large outpatient comparison of quetiapine and risperidone mentioned earlier,(9) the odds of requiring an anti-EPS medication was 5.6 times as high with risperidone as with quetiapine (p < 0.001).
(1)Conley RR, Brecher MB. Risperidone versus olanzapine in the treatment of patients with schizophrenia or schizoaffective disorder. Presented at the 1999 Annual Meeting of the American Psychiatric Association, Washington, DC, May 1999.
(2)Tran PV, Hamilton SH, Kuntz AJ, Potvin JH, Andersen SW, Beasley C, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407-18.
(3)Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-96.
(4)Knegtering H, Blijd C, Boks M. Sexual dysfunction and prolactin levels in patients using risperidone or olanzapine [Abstract]. Schizophr Res 2000;41:196.
(5)Kleinberg DL et al. Prolactin levels and adverse effects in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61.
(6)Sikich L, Williamson K, Malekpour A, Bashford RA, Hooper S, Sheitman B, et al. Interim results of a randomized controlled trial of haloperidol, risperidone, and olanzapine in psychotic youth. Presented at the 38th annual meeting of the American College of Neuropsychopharmacology, Acapulco, Mexico, December 1999.
(7)Arvanitis LA, Miller BG. Multiple fixed doses of "Seroquel" (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry 1997;42:233-46.
(8)Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CGG. Quetiapine in patients with schizophrenia: a high- and low-dose double-blind comparison with placebo. Arch Gen Psychiatry 1997;54:549-57.
(9)Reinstein MJ, Bari MA, Ginsberg LD, Sandler NH, Mullen JA. Quetiapine fumarate and risperidone in outpatients with psychotic disorders: results of the QUEST trial. Presented at the 1999 Annual Meeting of the American Psychiatric Association, Washington, DC, May 1999.
Risperidone is most effective and best tolerated at doses of 3-6 mg per day given for 3-6 weeks; higher amounts result in more extrapyramidal side effects (EPS), less improvement in negative symptoms, and longer length of hospital stay.(1-6) The starting dose of risperidone usually recommended for patients receiving their first exposure to an antipsychotic is 0.5 mg twice daily, which may be increased to 1 mg bid at day 2. The titration is to reduce the risk of alpha-blockade-related postural blood pressure changes. For patients with acute exacerbations of schizophrenia, previously treated with an antipsychotic, the dose may be doubled. Half these doses may be used in the elderly or infirm. Any dose of risperidone that produces EPS is probably higher than ideal for that patient.(1,5)
For acute inpatients, the dose may be raised to the level of 6 mg per day if tolerated by 1 week, or to a dose which produces no more than minimal EPS, whichever is lower. Higher doses, up to the PDR maximum of 16 mg, are sometimes used in treatment-resistant patients but again this is probably only useful if absolutely no EPS is seen at the lower doses. Some patients may get no EPS at lower doses and require higher doses if they are on another medication which induces metabolism of risperidone, such as carbamazepine. Other patients will be very sensitive to low doses and develop EPS or other side effects on 1 mg per day or less, due to the presence of a Cytochrome P450 2D6 or 3A4 inhibitor. Consult our P450 Drug Interactions program.
Among the new generation antipsychotics, risperidone comes the closest to having the side effect profile of a typical, parkinsonism-producing neuroleptic compared to the others, but at low doses (e.g. - 4 mg or less) these side effects are infrequent and as noted, clinical response is more favorable. Prolactin elevation is marked, and perhaps greater than that seen with the typical neuroleptics. Other side effects included agitation, anxiety, insomnia, headache and nausea. The agitation can look like akathisia, or it may present as hypomania or mania, a problem which has occurred with olanzapine as well. It is unclear whether these reports represent true side effects of the atypicals or coincidental exacerbations of the patient's underlying condition.
In a study of Chinese patients on Taiwan, with acute exacerbation of schizophrenia, 40% could not tolerate a dose of 6 mg per day due to side effects. When their dose was lowered to a mean of 3.6 mg they tolerated it and response was excellent. 30 of 31 patients completed this prospective, open label trial which encouraged physicians to find a dose that was tolerable, and response (20% reduction of PANSS) was 92% at the lower dose, vs 52% for those who stayed at 6 mg.(3) However, the results are confounded somewhat by the fact that the lower dose group had fewer hospitalizations. Thus, these results must be confirmed in better controlled studies using homogeneous populations. Nonetheless, it appears that Chinese and other East Asian ethnic individuals (and many Africans) usually need somewhat lower doses of antipsychotics metabolized by cytochrome 2D6 enzyme (such as risperidone), probably because 35-50% have a less active form of the 2D6 enzyme, rendering them "Slow Metabolizers" (SM's).(7) By contrast poor metabolizers (PM's) are comparatively rare among Asians, being found in 1-6% compared to 5-10% in Caucasians. PM's are the patients who will get EPS even on on very low doses of risperidone, and you always have to be on the lookout for them.
A PET scan study(8) confirmed that, in first-episode and drug free patients, risperidone at 6 mg per day produced EPS in almost everyone and dopamine D2 receptor occupancy averaging 82%, whereas at risperidone 3 mg, EPS were usually not present and the average D2 occupancy was 72%. Previous studies have shown that the optimal D2occupancy level for maximizing benefits and minimizing EPS is 70-80%.
¹Kopala LC, Good K, Honer WG. Extrapyramidal signs and clinical symptoms in first episode schizophrenia: response to low-dose risperidone. Journal of Clinical Psychopharmacology 1997; 17:308-313.
²Love RC, Conley RR, Kelly DL, Bartko JJ. A dose-outcome analysis of risperidone. Journal of Clinical Psychiatry 1999; 60:771-775.
(3)Lane H-Y, Chiu W-C, Chou JC-Y, Wu S-T, Su M-H, Chang W-H. Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels. Journal of Clinical Psychiatry 2000; 61:209-214.
(4)Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Schizophrenia Bulletin 1999; 25:721-729.
(5)Williams R. Optimal dosing with risperidone: updated recommendations. J Clin Psychiatry 2001;62(4):282-289.
(6)Lane H-Y et al. A pilot double-blind, dose-comparison study of risperidone in drug-naive, first-episode schizophrenia. J Clin Psychiatry 2001;62(12):994-995
(7)Pi EH, Gray GE. Ethnopsychopharmacology for Asians. In: Ruiz P, Ed. Ethnicity and psychopharmacology. Volume 19, Review of Psychiatry. American Psychiatric Press. Washington, D.C. 2000:91-113.
(8)Nyberg S, Eriksson B, Oxenstierne G, Halldin C, Farde L. Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. Am J Psychiatry 1999;156:6:869-875
Olanzapine is most efficacious when started and continued at 10-15 mg over a period of six weeks.(1-2) The dose for healthy, non-smoking adults with first-episode schizophrenia should probably be lower, however. Smoking increases olanzapine clearance by 40%, according to the package insert; among patients with schizophrenia, 58-88% are smokers.(3) Female gender decreases clearance by 30%, also according to the package insert. Therefore, an even lower dose might be appropriate for non-smoking women. Seizure risk is 0.9% in premarketing studies, which also approaches the rate with low-dose clozapine, and is higher than the 0.3% with risperidone. EPS occur, especially above 10 mg per day, but are uncommon. Orthostatic hypotension is the least of the three, thus enabling initiation of treatment at full dose. Anticholinergic effects appeared significant in in-vitro studies, but this has not been confirmed in patient experience: in direct comparisons of olanzapine with risperidone, there was hardly any difference in anticholinergic side effects.(4,5) Liver function tests may go up. There is minimal prolactin elevation with doses at 20 mg per day or less.
There has been some enthusiasm for exceeding the current PDR maximum dose of 20 mg in treatment-resistant cases. There may be greater efficacy at the higher doses such as 30 or even 40 mg.(6,7) although this study has elicited controversy because the olanzapine arm of the study was added later in time and it is unclear if the same patient population received olanzapine compared to the controls treated earlier. At higher doses, prolactin levels rise substantially, and other side effects such as weight gain, liver enzyme elevation, and EPS may occur more frequently, so these will have to be monitored more closely.(8) Consistent with these clinical findings, a PET study found higher D2 receptor occupancy at higher doses of olanzapine, and this higher occupancy was correlated with increased depression and "negative subjective experience" as measured by a "Subjective Well Being Under Neuroleptic Treatment Scale."(9) Thus, use of higher than approved doses of olanzapine may be associated with significant side effects that offset any apparent additional benefits, similarly to what has been demonstrated for typical neuroleptic antipsychotics.(10)
Safety monitoring guidelines: In view of the link between elevations of triglycerides and cardiovascular risks, the following olanzapine procedures are recommended [HIGH Confidence]:(11)
¹Beasley CMJ, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996; 14:111-123.
²Tollefson GD, Beasley CM, Jr., Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. American Journal of Psychiatry 1997; 154:457-465.
³Kelly C, McCreadie RG. Smoking habits, current symptoms, and promorbid characteristics of schizophrenic patients in Nithsdale, Scotland. American Journal of Psychiatry 1999; 156:1751-1757.
(4)Tran PV, et al. Double-blind comparison of olanzapine vs risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17:407-18.
(5)Conley RR et al. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001;158(5):765-74.
(6)Citrome L et al. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatric Services 2001;52(11):1510-1514
(7)Lindenmeyer J-P et al. Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial. J Clin Psychopharmacol 2001;21(4):448-453
(8)Bronson BD, Lindenmayer J-P. Adverse effects of high-dose olanzapine in treatment-refractory schizophrenia. J Clin Psychopharmacol 2000;20(3):382-384.
(9)de Haan L et al. Subjective experience and striatal Dopamine D2 receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone. Am J Psychiatry 2000;157:1019-1020.
(10)McEvoy JP, Hogarty GE, Steingard S. Optimal dose of neuroleptics in acute schizophrenia: a controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 1991;48:739-745.
(11)Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;21:369-374.
Quetiapine was found to be as efficacious as haloperidol in a fixed dose study involving 361 patients hospitalized with acute exacerbation of chronic schizophrenia. The patients were randomly assigned to either 12 mg of haloperidol or to 75, 150, 300, 600, or 750 mg of quetiapine per day.(1) Patients reached their predetermined dose by the end of week 1. After six weeks of treatment, patients taking the four highest doses of quetiapine did not differ significantly in Brief Psychiatric Rating Scale (BPRS) total score from patients taking haloperidol, but they scored significantly better than those taking placebo. There was a non-significant trend favoring the three highest doses of quetiapine over haloperidol on improvement in positive symptoms, starting at three weeks. Another investigation of quetiapine, (2) with 286 similar patients, had a placebo control but no antipsychotic comparison. This study used two flexible dose ranges of quetiapine, and found that 488 mg was more efficacious than 248 mg.
On the basis of these and other studies, it has been proposed that optimal dosing with quetiapine would be to start with 25 mg bid, raising the dose to 100 mg per day on the second day, 200 on the third day, 300 on the fourth, and 400 mg on the fifth day.(3) Postural dizziness from alpha-adrenergic blockade will sometimes prevent rapid dosage increase, however. Seizures occurred 0.8% in premarketing studies, which is similar to olanzapine and higher than risperidone's 0.3%. Sedation is fairly prominent as an effect. Liver function tests are elevated about as often as occurs with olanzapine and more frequently than risperidone. Anticholinergic effects are insignificant usually. Focal cataracts (different from the more usual posterior subcapsular cataracts seen from steroid use, sunlight, etc.) have been found in studies with dogs, but not reported in humans. Nevertheless, cataract examination by the patient's primary care physician should be done at baseline and at six month intervals. No significant prolactin elevation.
¹Arvanitis LA, Miller BG, Seroquel-Trial-Study-Group. Multiple fixed doses of "Seroquel" (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biological Psychiatry 1997; 42:233-246.
(2)Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CGG. Quetiapine in patients with schizophrenia: a high- and low-dose double-blind comparison with placebo. Archives of General Psychiatry 1997; 54:549-557.
(3)Stahl SM. Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. Journal of Clinical Psychiatry 1999; 60:31-41.
Before using ziprasidone, the clinician should follow the recommendations in the package insert regarding cardiovascular safety issues. These may be summarized as follows:
*Formula for calculating QTc from EKGs that do not display the QTc results: First, convert QT to milliseconds, e.g. - if it says 0.4 for QT, this is 400 ms. Then: QTc = QT + 1.75(ventricular rate in beats/min. - 60)
Dosing of Ziprasidone: While the ziprasidone package insert recommends starting at 20 mg twice daily (WITH FOOD), three out of four acute treatment studies in patients with schizophrenia failed to show superiority of 20 mg bid to placebo.(1) At 40 mg bid and perhaps especially at 80 mg bid, robust superiority to placebo is seen, and equivalence to haloperidol. Therefore, it is commonly recommended to raise the dose, as tolerated, every 1-2 days to 80 bid for the routine case of an acutely ill hospitalized patient with schizophrenia.(2) If this is a first episode patient, try perhaps half the routine dose: this is based on evidence with the use of other antipsychotics. If this is a stable outpatient being switched from another antipsychotic to ziprasidone, evidence suggests (2-4) that most patients may be started on 40 bid and adjusted up to 80 mg bid after two days. Later, the ziprasidone could be reduced, as tolerated, back as low as 20 bid for long-term maintenance. At the same time, the other antipsychotic may be continued at full dose for the first two days, and then decreased by 50% for the next 5 days, and then stopped.
¹Bagnall A-M, Lewis RA, Leitner ML. Ziprasidone for schizophrenia and severe mental illness. Cochrane Library 4. Oxford, England: Update Software, 2000. (On web at www.cochrane.org)
²Weiden PJ. Ziprasidone: a new atypical antipsychotic. Journal of Psychiatric Practice 2001;7(2):145-154.
³Hirsch SR, Benattia I, Moilson M. Replacement of depot antipsychotic therapy with oral ziprasidone. Presented at the 41st annual NCDEU meeting, Phoenix, Arizona, May 28-31, 2001.
(4)Stip E. Haloperidol-to-ziprasidone switching strategies in schizophrenia. Presented at the 41st annual NCDEU meeting, Phoenix, Arizona, May 28-31, 2001.
Aripiprazole (Abilify) became available at the end of 2002 in the USA. It is an important new option in terms of side effect profile compared to other second generation antipsychotics. Its efficacy seems solid but more comparisons with the others are needed. Full prescribing information may be found in the package insert and Physicians Desk Reference, issued November 2002.
Aripiprazole is usually given as a 10 or 15 mg dose given once a day. It also comes with a 20 and 30 mg dose. The 75 hour half-life makes aripiprazole among the longer half-life antipsychotics. Steady state plasma levels are reached in about 2 weeks, so patience is required in waiting for the drug to reach full effect. The Kane et al study¹ compared starting doses of 15 mg vs. 30 mg and found that the 15 mg dose produced equivalent or non-significantly better results than the 30 mg at 1 week and all subsequent weeks of the 4 week study. So, there is no advantage, and perhaps a disadvantage to a "loading dose" strategy of starting with 30 mg.
Aripiprazole is a substrate at cytochrome P450 3A4 and 2D6. Thus, there are significant drug interaction issues. For example, if given with a potent 2D6 inhibitor like paroxetine or fluoxetine, use 1/2 the usual dose. If given with a 3A4 inducer like carbamazepine, use double the dose. Also note that 8% of the population are Poor Metabolizers of 2D6. They will get 60% higher levels of aripiprazole compared with other patients. No dose adjustment needs to be made, generally, for patients with renal or liver disease (despite the liver metabolism), the elderly, or with different races, genders, or smoking status.
In the Kane et al¹ study, the two doses of aripiprazole, 15 and 30 mg, were compared with haloperidol 10 mg in acute schizophrenia and schizoaffective disorder. The 15 mg dose, which did better than 30, stayed close to haloperidol on the PANSS and finally separated from it by week four. However, on the positive symptom cluster of the PANSS, haloperidol stayed ahead (non-significantly) at all points. Thus, the advantage over haloperidol is due to negative symptoms. After one week, haloperidol appeared clinically significantly better than either dose of aripiprazole. Thus, aripiprazole does not appear to be a particularly rapidly-acting medication.
In another study, unpublished at this time, by Saha et al,² aripiprazole 20 mg and 30 mg were compared with risperidone 6 mg. The risperidone was insignificantly better at weeks 2,3,4. The two doses of aripiprazole had equivalent effects. One might wonder if a 10 or 15 mg dose might have competed more favorably with the risperidone.
Side effects are low in the research study reports. There was a 1.5 lb weight gain over 4 weeks (5.7 lb over 1 year in a follow up study) This is comparable to haloperidol. Dose-related somnolence was found only with the 30 mg dose. Insomnia affected 5% more patients than placebo, lightheadedness 4% more. Two cases of neuroleptic malignant syndrome were found out of 1,000 patients treated, which seems a bit high. Orthostatic changes are seen occasionally so it must be used with caution in patients with recent heart attack, ischemia, or cerebrovascular disease. Seizures occurred in 0.1%, low compared to other antipsychotics. Elderly patients with Alzheimer's disease could be a high risk group: 4% died of various causes in one study compared with none on placebo (N=200 patients). It may have been a problematic sample, but if used in this population patients (or their guardians) should be informed.
¹Kane MH et al. Efficacy and safety of aripiprazole and haloperidol vs placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-771
²Saha A et al. Efficacy and safety of aripiprazole and risperidone vs. placebo in patients with schizophrenia and schizoaffective disorder. Presented at the 7th World Congress of Biological Psychiatry, Berlin, July 1-6, 2001.
Other new atypical antipsychotics are coming.
¹
²
Discontinuing an antipsychotic can result in exacerbations within days to months after discontinuation. (1) This confounds interpretation of the results of switching to a new antipsychotic: withdrawal from the old one may lead to problems before the new one has had time to work. A comprehensive review found that slow discontinuation of the previous antipsychotic did not seem to limit or delay relapses as much as one might have hoped (unlike lithium discontinuation, where slow discontinuation clearly prevents relapses). (2) Nevertheless, we advocate avoiding abrupt discontinuation of the previous antipsychotic, unless one has to do so because of acute toxicity. We prefer adding the new medication starting at a low dose and gradually increasing to a full dose, and then starting a 2-3 week taper of the old medication from 1 to 3 weeks after the new drug is clearly being tolerated well. When switching to olanzapine, however, you may start with the full intended dose of olanzapine (e.g. 10 mg for a stabilized outpatient) and then begin the taper of the original antipsychotic in 2-3 weeks.(3-4)
The duration of the trial should ideally be eight weeks to be considered adequate. If the patient is gradually improving, one should wait until that improvement has plateaued before considering further dosage increase of the new antipsychotic.
Some patients are rapid responders to antipsychotics with significant improvement occurring in days to a week. Others, even first onset patients, may require many months at adequate doses to achieve partial (much less full) response.(5) However, especially in the acute inpatient setting, clinical or administrative pressures often make it impractical to wait this long.
If the patient shows very little or no benefit during the first few weeks, the chance of missing a response by not waiting longer is probably small. However, if the patient shows steady, although only moderate improvement, it may be worthwhile to resist the pressure to try to hurry things along by increasing the dose, adding additional medications, or changing the drug. Try to stay with the same dose for the full eight weeks, or for longer until the response has clearly plateaued. If there are side effects developing that are not responding to dosage adjustment or other treatment and are likely in the long run to significantly impair outcome, then earlier movement to the next monotherapy treatment option would be justified.
(1)Janicak PG et al. Use of Antipsychotics (Chapter 5). Principles and Practice of Psychopharmacotherapy, Third Edition. New York, Lippincott Williams and Williams, 2001. [contains excellent discussion of the literature on the time course of relapse after stopping an antipsychotic]
(2)Viguera AC, Baldessarini RJ, hegarty JD, et al. Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Arch Gen Psychiatry 1997;54:49-55.
(3)Kinon BJ, Basson BR, Gilmore JA, et al. Strategies for switching from conventional antipsychotic drugs or risperidone to olanzapine. J Clin Psychiatry 2000;61:833-840.
(4)Weiden PJ, Aquila R, Dalheim L, Standard JM. Switching antipsychotic medication. J Clin Psychiatry 1997;58[suppl 10]:63-72
(5)Lieberman J, Jody D, Geisler S, et al. Time course and biologic correlates of treatment response in first-episode schizophrenia. Arch Gen Psychiatry 1993;50:369-376.