Even during the acute phase of treatment, it is important to consider the long-term consequences of medication selection. In most instances, patients will continue to take the antipsychotic used to treat acute symptoms for maintenance care as well. Thus, acute treatment selection should take into account the effectiveness, tolerability, accessibility, and cost of the antipsychotic drugs for continued care. Unfortunately, recent clinical efficacy studies have tended to accentuate, rather than resolve, debate on these issues.
The Clinical Antipsychotic Trials of Intervention Effectiveness study confirmed the long-standing observation that both conventional and atypical antipsychotics are efficacious for the maintenance treatment of schizophrenia; it has also renewed attention to the older drugs, especially perphenazine(Drug information on perphenazine).15 One surprising finding of the study was that perphenazine, an intermediate-potency conventional neuroleptic included in the study on the basis of its relatively favorable side-effect profile, was tolerated about as well as the newer drugs, although its association with EPS was higher. Of note, the study also demonstrated that although there were differences among the drugs in how well they work for maintenance therapy, no single medication was clearly superior for all patients.
The more recent Cost Utility of the Latest Antipsychotics in Severe Schizophrenia 1 study found that the 2 classes of drugs were comparable on quality-of-life and cost-effectiveness measures.16 The 2 studies tend to support the argument that atypical drugs (clozapine excepted) are no more or less effective than the older agents for acute or maintenance treatment. Currently, the primary basis on which atypical antipsychotics can be recommended is their reduced risk for short- and long-term movement disorders, including EPS17 and tardive dyskinesia (TD).18
As already noted, however, these studies do not predict the treatment response of individual patients, and more personalized criteria for treatment selection must be used. Among oral medications, drug selection may reasonably be based on the patient's earlier experience with the medication, including both the drug's effectiveness and its side effects. A patient who has previously done well on a particular medication should be given that medication again. Patients who had troubling adverse effects should be given a medication with the lowest propensity to cause those problems. A comparison of relative risk for adverse effects for the first-line atypical drugs in acute phase trials is shown in Table 1.
Patients who have not responded well to a prior trial of a particular antipsychotic should be switched to another antipsychotic, either atypical or conventional. There is no consensuson how many different antipsychotics should be used before a trial of clozapine(Drug information on clozapine) is justified, but most guidelines recommend at least 2 atypical medications, and some suggest at least 1 conventional drug.19 There is little basis for the common practice of combining antipsychotics and none for doing so in the acute phase of treatment.
Selection of a medication for a patient without prior treatment may be based on physician experience and preference, taking into account the adverse effects for which the patient is most at risk. For example, a patient with obesity, diabetes, or other metabolic factors should be given a medication with lower risk for metabolic syndrome. A patient with a history of cardiac problems and multiple heart medications should be given an antipsychotic with fewer potential interactions with these drugs. Patients with preexisting movement disorders should be directed to medications with a lower propensity to cause EPS.
For patients requiring long-acting medication, a transition from an oral to an injectable depot formulation should be initiated. Currently, fluphenazine(Drug information on fluphenazine) decanoate, 12.5 to 50 mg to a maximum dosage of 50 mg/wk,20 and haloperidol(Drug information on haloperidol) decanoate, 50 to 200 mg to a maximum dosage of 200 mg/4 wks21 are available; the atypical drug risperidone(Drug information on risperidone) is available in a long-acting microsphere formulation, 25 to 50 mg to a maximum dosage of 50 mg/2 wks.22 Adverse effects of the medications are comparable to those of the oral preparations. Oral dosing should continue until at least 3 injections of haloperidol or fluphenazine have been given and for 3 to 4 weeks after the initial dose of long-acting risperidone. The primary advantage of the conventional agents is lower cost, and that of risperidone is its relatively benign EPS profile23 and the potentially lower risk of TD.
In contrast to the maintenance phase of treatment in which there is ample time to evaluate each change of medication dose, the acute phase requires an initial dose selection when it may not be clear how much medication will be effective and well tolerated. Physicians may also experience pressure from payers, family, or even the patients themselves to accelerate the pace of improvement with higher doses of medication when it is not apparent whether an incomplete response is caused by inadequate dosing or inadequate time taking the medication. The issue is complicated by the difficulty of establishing a lowest effective dose in the later phases of treatment without placing the patient at risk for relapse.
As a recommendation for initial treatment, one reasonable approach is to titrate quickly to the most common dose range found effective in controlled trials, then give the patient 3 to 4 weeks to respond. During that time, dose adjustments can be made in response to adverse effects, acute situations, extreme patient distress from persistent symptoms, or other clinical factors. In general, dose adjustment within standard ranges is preferred to the use of adjunctive medication or antipsychotic polypharmacy, which have limited data to support their effectiveness and introduce the potential for additional adverse effects and drug interactions. Reasonable ranges for the initial phase of treatment are given for haloperidol and the atypical medications in Table 2. Higher or lower doses may be appropriate in some cases but require a specific rationale, such as a history of side effects, previous superior response at a different dose, or clear failure to respond within the standard dosage range.
The resolution of acute symptoms and establishment of an effective and reasonably well-tolerated dosage of antipsychotic medication are the central issues in this phase of schizophrenia treatment. Once these goals are met, the patient may begin the transition to maintenance treatment, including hospital discharge, selection of psychosocial interventions, and follow-up planning. The foundation for a successful course of maintenance treatment is often the quality of treatment decisions and planning in the acute phase, giving it importance well beyond the few days or weeks it generally entails. These guidelines should thus be viewed as having importance for the entire course of treatment as they set the stage for the maintenance therapy that is to follow for effective schizophrenia management.
Dr Jibson is clinical associate professor in the department of psychiatry at the University of Michigan in Ann Arbor. He reports that he is on the speakers' bureaus of AstraZeneca, Janssen, and Bristol-Myers Squibb (in order of compensation received in the last 24 months).
Drugs Mentioned in This Article
Aripiprazole(Drug information on aripiprazole) (Abilify)
Fluphenazine (Prolixin Decanoate)
Olanzapine(Drug information on olanzapine) (Zyprexa)
Perphenazine (Etrafon, Trilafon, Triavil)
Ziprasidone(Drug information on ziprasidone) (Geodon)
1. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50:884-897.
2. Glazer WM, Dickson RA. Clozapine reduces violence and persistent aggression in schizophrenia. J Clin Psychiatry. 1998;59(suppl 3):8-14.
3. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam(Drug information on lorazepam), or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med. 1997;15:335-340.
4. Keck PE Jr, Strakowski SM, McElroy SL. The efficacy of atypical antipsychotics in the treatment of depressive symptoms, hostility, and suicidality in patients with schizophrenia. J Clin Psychiatry. 2000;61(suppl 3):4-9.
5. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-157.
6. Abilify [package insert]. New York: Bristol-Myers Squibb; revised October 2006.
7. Zyprexa [package insert]. Indianapolis: Eli Lilly & Co; 2006.
8. Risperdal [package insert]. Titusville, NJ: Janssen, L.P.; 2007.
9. Geodon for Injection [package insert]. New York: Pfizer; 2007.
10. Haldol [package insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc; 2005.
11. Palmer BA, Pankratz VS, Bostwick JM. The lifetime risk of suicide in schizophrenia: a reexamination. Arch Gen Psychiatry. 2005;62:247-253.
12. Kim CH, Jayathilake K, Meltzer HY. Hopelessness, neurocognitive function, and insight in schizophrenia: relationship to suicidal behavior. Schizophr Res. 2003;60: 71-78.
13. Meltzer HY. Treatment of suicidality in schizophrenia. Ann NY Acad Sci. 2001;932:44-58.
14. Ayuso-Gutierrez JL, del Rio Vega JM. Factors influencing relapse in the long-term course of schizophrenia. Schizophr Res. 1997;28:199-206.
15. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.
16. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006; 63:1079-1087.
17. Tandon R, Jibson MD. Extrapyramidal side effects of antipsychotic treatment: scope of problem and impact on outcome. Ann Clin Psychiatry. 2002;14:123-129.
18. Nasrallah HA. Focus on lower risk of tardive dyskinesia with atypical antipsychotics. Ann Clin Psychiatry. 2006;18:57-62.
19. Constantine RJ, Richard SM, Surles RC, et al. Optimizing pharmotherapy of schizophrenia: tools for the psychiatrist. Curr Psychosis Ther Rep. 2006;4:5-11.
20. Fluphenazine decanoate injection [package insert]. Bedford, Ohio: Bedford Laboratories; 1998.
21. Haldol decanoate [package insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc; 2005.
22. Risperdal Consta [package insert]. Titusville, NJ: Janssen, L.P.; 2003.
23. Kane JM, Eerdekens M, Lindenmayer JP, et al. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry. 2003;160:1125-1132.
24. Tarsy D, Baldessarini RJ, Tarazi FI. Effects of newer antipsychotics on extrapyramidal function. CNS Drugs. 2002;16:23-45.
25. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27:596-601.
26. Allison DB, Mentore JL, Moonseong H, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686-1696.
27. Stanniland C, Taylor D. Tolerability of atypical antipsychotics. Drug Safety. 2000;22:195-214.
28. Glassman AH. Schizophrenia, antipsychotic drugs, and cardiovascular disease. J Clin Psychiatry. 2005;66 (suppl 6):5-10.
- Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.
- Stanniland C, Taylor D. Tolerability of atypical antipsychotics. Drug Safety. 2000;22:195-214.