Michael D. Jibson, MD, PhD

Acute episodes of schizophrenia are characterized by active psychosis, with accompanying exacerbation of negative symptoms, mood disturbance, and cognitive impairments. The pervasiveness and severity of symptoms is subjectively distressing, damaging to relationships, incompatible with most employment, and often inconsistent with any level of independent functioning-resulting in hospital admission. Furthermore, much of the functional deterioration associated with chronic schizophrenia occurs during acute episodes, limiting the patient's potential for a return to previous employment or living situation.

Specific treatment goals in acute schizophrenia are the following:

	Ensuring the safety of the patient andthe caregiver.

	Evaluating and treating precipitating factors.

	Rapidly resolving the patient's psychotic symptoms.

	Establishing an effective and well-tolerated medication regimen.

	Beginning transitional phase to maintenance treatment.

Because the primary goal is to maintain a safe environment for the patient and for caregivers, it is important that both aggression and suicidality are quickly addressed during episodes of acute schizophrenia.

MANAGEMENT OF ACUTE AGITATION AND AGGRESSION 


Psychotic agitation is a state of heightened arousal, anxiety, and potential for aggression-often in response to delusional ideas, hallucinatory suggestions, or attempts at intervention by health care providers or others. Patients at highest risk are those with persecutory delusions, thought disorganization, and high levels of impulsivity.

 Rapid control of agitation is essential before starting other steps in treatment.

Antipsychotic medications, generally in conjunction with benzodiazepines, represent the most effective approach to the acutely agitated patient.

 Several medication options are available, including conventional and atypical antipsychotics in oral and injectable formulations. Oral medications have the advantages of being less invasive, preserving a greater degree of patient autonomy, being more acceptable to patients, and carrying less risk to patients and staff. There is little evidence to suggest that response times are significantly slower with oral drugs than with injectable drugs.


Oral antipsychotics are available in standard tablets, orally disintegrating tablets, and liquid concentrates. Although any of these formulations may be used effectively, the orally disintegrating tablets have the advantages of being easy to administer, requiring minimal cooperation on the part of the patient, and providing assurance to staff that the medication was not “cheeked” or spit out.

Three antipsychotics are currently available in orally disintegrating tablets and are appropriate for treatment of acute agitation. Aripiprazole is available in 10 and 15 mg tablets and may be used at 2-hour intervals up to 30 mg/d.

 Olanzapine is available in doses of 5 to 20 mg and may be used at intervals of 2 to 4 hours up to 20 mg/d.

 Risperidone is available in doses from 0.5 to 4 mg and is generally used in 1- to 2-mg increments with a maximum recommended dosage of 8 mg/d.

 None of these medications are absorbed transmucosally; they must be swallowed, and each has the same pharmacokinetics as standard tablets. There is no evidence of differences among the drugs in efficacy for agitation or psychosis in the acute phase of illness, and all are well tolerated for short-term use.


If the patient is unable or unwilling to cooperate with an oral medication regimen, intramuscular injection may be required. Most conventional antipsychotics and 3 atypical agents-aripiprazole, 9.75 mg to a maximum of 30 mg/d6; olanzapine, 10 mg to a maximum of 30 mg/d7; and ziprasidone, 10 to 20 mg to a maximum of 40 mg/d9-are available for short-term intramuscular administration. The dose of haloperidol is 2 to 5 mg to a maximum recommended dosage of 20 mg/d.10 Haloperidol has the advantages of low cost and ease of preparation, making it readily available in most settings. It has the disadvantage of high risk for extrapyramidal syndrome (EPS), eg, acute dystonia, akathisia, and bradykinesia, which may complicate the patient's acute presentation.

The injectable atypical drugs are effective and well tolerated for short-term use in this population. The atypical drugs have the advantage of lower risk for EPS, but olanzapine and ziprasidone require additional time to prepare.

 Ziprasidone has a refrigerated storage life of 7 days, allowing it to be prepared and stored weekly, which may be a practical alternative in centers with high use of the drug.

 Of note, QTc changes have not been significant with injectable ziprasidone.


Benzodiazepines should be considered as an adjunct to both oral and injectable antipsychotics in the patient who is acutely agitated.

 Although they have no antipsychotic efficacy, their sedative and anxiolytic properties work well for agitation. Benzodiazepines differ in route of administration, potency, and pharmacokinetics, but not in spectrum or degree of efficacy. Thus, any benzodiazepine may be used for oral administration. In contrast, only lorazepam is available for intramuscular use. The typical dosage of lorazepam, whether oral or intramuscular, is 2 mg every 30 minutes to 2 hours, to a maximum recommended dosage of 12 mg in 12 hours.

 Most patients respond after 1 or 2 doses.

 
Suicide risk in schizophrenia is highest in the acute phase of illness, representing about 5% of all deaths among these patients.

 Perhaps counterintuitively, the greatest risk is experienced by higher-functioning, more insightful patients, as well as by those with more depressive symptoms and higher levels of substance abuse.

 In contrast to the risk of aggression, suicide is most likely at the end of the acute phase of illness as the patient prepares for the transition to maintenance care. Among pharmacologic treatments, only clozapine has been shown to reduce suicide risk, although the basis for the improvement is unclear.


A variety of factors have been associated with acute schizophrenic episodes, including substance abuse, psychosocial stressors, medical illness, and nonadherence to treatment. Among patients with previously diagnosed schizophrenia, failure to comply with prescribed treatment was shown to be responsible in 75% of patients who relapsed.

It may be useful in these patients to determine the basis for suboptimal compliance with treatment. If it is due to poor effectiveness or to side effects the patient finds intolerable, a switch to an alternative medication is reasonable. If the patient tolerates and responds to the medication but has other reasons for rejecting treatment, such as denial of illness, lack of insight, or poor family support, a transition to long-acting medication may be appropriate.


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.

 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.

 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).

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 

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 is justified, but most guidelines recommend at least 2 atypical medications, and some suggest at least 1 conventional drug.

 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 decanoate, 12.5 to 50 mg to a maximum dosage of 50 mg/wk,20 and haloperidol decanoate, 50 to 200 mg to a maximum dosage of 200 mg/4 wks

 are available; the atypical drug risperidone is available in a long-acting microsphere formulation, 25 to 50 mg to a maximum dosage of 50 mg/2 wks.

 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 profile


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 

. 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).


Aripiprazole (Abilify)
Clozapine (Clozaril)
Fluphenazine (Prolixin Decanoate)
Haloperidol (Haldol)
Lorazepam (Ativan)
Olanzapine (Zyprexa)
Perphenazine (Etrafon, Trilafon, Triavil)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)

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.


Glazer WM, Dickson RA. Clozapine reduces violence and persistent aggression in schizophrenia. J Clin Psychiatry. 1998;59(suppl 3):8-14.


Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med. 1997;15:335-340.


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. 


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. 


 Abilify [package insert]. New York: Bristol-Myers Squibb; revised October 2006.


Zyprexa [package insert]. Indianapolis: Eli Lilly & Co; 2006.


 Risperdal [package insert]. Titusville, NJ: Janssen, L.P.; 2007.


Geodon for Injection [package insert]. New York: Pfizer; 2007.


Haldol [package insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc; 2005.


Palmer BA, Pankratz VS, Bostwick JM. The lifetime risk of suicide in schizophrenia: a reexamination. Arch Gen Psychiatry. 2005;62:247-253.


 Kim CH, Jayathilake K, Meltzer HY. Hopelessness, neurocognitive function, and insight in schizophrenia: relationship to suicidal behavior. Schizophr Res. 2003;60: 71-78.


 Meltzer HY. Treatment of suicidality in schizophrenia. Ann NY Acad Sci. 2001;932:44-58.


 Ayuso-Gutierrez JL, del Rio Vega JM. Factors influencing relapse in the long-term course of schizophrenia. Schizophr Res. 1997;28:199-206.


 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. 


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.


 Tandon R, Jibson MD. Extrapyramidal side effects of antipsychotic treatment: scope of problem and impact on outcome. Ann Clin Psychiatry. 2002;14:123-129.


 Nasrallah HA. Focus on lower risk of tardive dyskinesia with atypical antipsychotics. Ann Clin Psychiatry. 2006;18:57-62.


 Constantine RJ, Richard SM, Surles RC, et al. Optimizing pharmotherapy of schizophrenia: tools for the psychiatrist. Curr Psychosis Ther Rep. 2006;4:5-11. 


 Fluphenazine decanoate injection [package insert]. Bedford, Ohio: Bedford Laboratories; 1998.


 Haldol decanoate [package insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc; 2005.


 Risperdal Consta [package insert]. Titusville, NJ: Janssen, L.P.; 2003.


 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.


Tarsy D, Baldessarini RJ, Tarazi FI. Effects of newer antipsychotics on extrapyramidal function. CNS Drugs. 2002;16:23-45.


 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.


 Allison DB, Mentore JL, Moonseong H, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686-1696.


Stanniland C, Taylor D. Tolerability of atypical antipsychotics. Drug Safety. 2000;22:195-214.


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.

Author | Michael D. Jibson, MD, PhD

Articles

Pharmacotherapy of Acute Schizophrenia