May 2008

Three IM Antipsychotics
New intramuscular (IM) formulations of second-generation antipsychotics appear comparable and possibly superior in efficacy and safety to older agents, but are more expensive.

Baclofen for Alcohol Dependency with Liver Cirrhosis
Baclofen (Lioresal and others) shows efficacy in treating alcohol dependency with no adverse hepatic effects.

Antipsychotics to Treat Aggression in Patients with Intellectual Disability
A double-blind study finds little evidence to support the use of antipsychotics to treat aggression in patients with intellectual disability.

In Brief
Desvenlafaxine Approved for Depression; Olanzapine LAI Not Approved for Schizophrenia

Depression Infrequently Treated
Many patients with depression worldwide do not receive effective care.

Clozapine Plus Aripiprazole
Aripiprazole (Abilify) may be beneficial for patients with schizophrenia who respond only partially to clozapine (Clozaril and others).

Three IM Antipsychotics

May 2008

Three second-generation antipsychotics are now available in a rapid-acting intramuscular (IM) formulation: ziprasidone (Geodon), olanzapine (Zyprexa), and aripiprazole (Abilify). Their intended use is for agitation, typically in the face of a psychotic disorder such as schizophrenia or bipolar mania. Doctors have previously treated psychotic agitation with IM medications such as haloperidol (Haldol and others) and/or lorazepam (Ativan and others). Citrome analyzed the clinical trials that led to approval of the three new IM formulations to compare effect sizes and relative safety.1

The author examined data from nine double-blind, randomized, controlled clinical trials conducted by the drugs' manufacturers. Computing numbers needed to treat (NNT—an estimate of how many patients would have to be treated to achieve a specified benefit), Citrome found the strongest effect size (ie, the lowest NNT) for ziprasidone, 20 mg, and olanzapine, 7.5 or 10 mg, in the treatment of agitation associated with schizophrenia. Olanzapine, 10 mg, also showed a strong effect in treating agitation associated with bipolar mania.

For ziprasidone, there appears to be a dose-response relationship, in which the effect strengthens (NNT drops by half) when increasing from 10 to 20 mg. Similarly, for olanzapine, the NNT also drops by half when the dose increases from 2.5 to 7.5 mg. For aripiprazole, a dose-effect relationship was not evident among the three doses employed: 5.25 mg, 9.75 mg, and 15 mg for schizophrenia or bipolar mania. Ziprasidone, olanzapine, and aripiprazole all seemed comparable in efficacy to haloperidol and lorazepam in trials that employed active controls. In comparison with older agents, olanzapine appeared superior to haloperidol in one study and to lorazepam in another.

Number need to harm (NNH) measures adverse effects. Several achieved statistical significance: hypotension with olanzapine (NNH = 50, which means that 1 patient in 50 will experience hypotension); headache with ziprasidone and aripiprazole (NNH = 15 and 20, respectively), and nausea with aripiprazole (NNH = 17). The three second-generation agents seemed to cause fewer extrapyramidal events than haloperidol. Ziprasidone caused no clinically significant QTc increases.

Citrome points out that patients in clinical trials are usually less severely ill, have fewer comorbid medical conditions, and take fewer concomitant medications compared with patients in clinical practice. This limits the generalizability of the results from such studies.

Newer medications are more expensive than on-patent second-generation medicines. On the other hand, if one of the newer agents can be used singly, rather than a "cocktail" of multiple first-generation agents, which sometimes require antiparkinson medicines to control side effects, the costs may be more competitive.

The author urges monitoring of blood pressure and pulse in patients treated with IM olanzapine, and orthostatic hypotension in patients taking IM aripiprazole, especially when a benzodiazepine is used concomitantly. It remains to be seen whether the three IM second-generation antipsychotics will prove superior in clinical practice and be better tolerated than old standbys like IM haloperidol and lorazepam—enough to compensate for their increased costs.

1Citrome L: Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: A quantitative review of efficacy and safety. J Clin Psychiatry 2007;68:1876–1885.