Antipsychotics Side Effects

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The atypical antipsychotics like Zyprexa, Seroquel, Abilify and Geodon pose a risk of EPS (extra-pyramidal symptoms), sedation, weight gain, diabetes, impotence and raised prolactin, cognitive dulling, and heart rhythm irregularity. Some of these effects involve just one drug, others more than one.

EPS and Tardive Dyskinesia: An antipsychotic medication needs to occupy 65 percent of the brain's dopamine D2 receptors for resolution of psychotic symptoms, but if a drug reaches 80 percent occupancy, most patients will experience initial and often transient adverse motor effects, referred to collectively as EPS, including muscle stiffness and involuntary spasms).

Tardive dyskinesia refers to similar side effects that set in after about six months.

For the older antipsychotics such as Haldol, the narrow dose range makes it easy to overshoot the 80 percent occupancy threshold. With second-generation drugs, finding the target range with the right dose is easier.

A German study of six patients receiving both vitamins E and C found the vitamins reduced the tardive dyskinesia effects of the antipsychotics they were taking. High dose vitamin E with its pro-oxidative effects carries cardiac risks. Vitamin C may reduce this risk by interacting with vitamin E. A New York University study of 36 men with tardive dyskinesia found those who took high dose branched-chain amino acids, vital to muscle tissue maintenance, showed a significant reduction in their symptoms.

Older antipsychotics attach firmly to the D2 receptor and block it for a day while the atypicals bind loosely, allowing the normal transmission of the brain's dopamine (and thus permitting pleasure and arousal). The new atypical antipsychotic, Abilify (aripiprazole) - which in 2002 received approval for schizophrenia from the FDA - has high affinity to the dopamine receptors, but permits some dopamine to cross over to the postsynaptic cell, which largely avoids EPS.

With atypicals, risk of EPS and tardive dyskinesia is greatly reduced, but still remains a worry. According to Zyprexa's labeling, 32 percent of patients report at least one EPS effect at approx 15 mg a day, 25 percent at approx 10 mg a day, and 15 percent at approx 5 mg a day. Risperdal and Geodon also have dose-related EPS effects. Seroquel has no increase in EPS with any dose, though there is a small risk, and Abilify only has small initial akasthisia (a type of mental restlessness). Clozaril runs a negligible risk of EPS.

Dosing recommendations when the atypicals first hit the market were either too high or too low or too vague, but it is now generally accepted that the following doses equate to eight mg of the old generation Haldol: Zyprexa (15 mg), Seroquel (500 mg), Risperdal (three mg), Geodon (!00 mg), and Abilify (15 mg).

Recent studies have challenged the claim that the newer atypicals are more efficacious and have better side effects than the older antipsychotics. A 2000 Oxford analysis of 52 studies published in the British Medical Journal found no difference in effectiveness between the newer and older drugs. A 2003 German review published in The Lancet found only Clozaril had fewer side effects than the older drugs. A 2003 US Veterans Affairs study of 309 patients with schizophrenia or schizoaffective disorder taking either Zyprexa or Haldol for 12 months found "no significant differences" between the two groups in terms of schizophrenia symptoms, drop-out rates, quality of life, or EPS. Those on Zyprexa fared slightly better in terms of reduced akathisia (motor restlessness) and tardive dyskinesia, but encountered greater weight gain and significantly greater VA costs, ranging from $3,000 to $9,000 annually.

Other recent studies lend credence to the claims made by manufacturers of the atypicals:

A 2003 University of Chicago/Stanford meta-analysis of 124 trials found Clozaril, amisulpride (available in Europe), Risperdal, and Zyprexa "significantly more efficacious than first generation antipsychotics." Clozaril produced the best results. Other atypicals, however, including Seroquel, Geodon, Abilify, remoxipride, and sertindole were similar in efficacy to the older drugs such as Haldol. A 2003 Eli Lilly study comparing Zyprexa to Haldol found similar efficacy in manic patients, but better tolerability for Zyprexa (more on this further down). Finally, a multi-center meta-analysis of 11 long-term studies involving 2,769 patients receiving atypical antipsychotics or Haldol found that those on the atypicals had a reduced risk of tardive dyskinesia compared to those on Haldol (0.0 to 1.5 percent vs 5.4 percent), though the doses of Haldol in the studies were relatively high.

continue: Sedation, Sexual Dysfunction, Weight Gain and Diabetes

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Reviewed: 03/2006