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Pharmacotherapy of Acute Schizophrenia

Pharmacotherapy of Acute Schizophrenia

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.1

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.

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.2 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.3,4 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.5

Oral antipsychotics
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.6 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.7 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.8 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.

Intramuscular injection
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.7,9 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.9 Of note, QTc changes have not been significant with injectable ziprasidone.9

Benzodiazepines should be considered as an adjunct to both oral and injectable antipsychotics in the patient who is acutely agitated.3 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.3 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.11 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.12 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.13

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.14

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.


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