2nd-Generation Antipsychotics Cause Extrapyramidal Side Effects as Much as 1st-Generation

Kermit Cole

According to researchers from Yale and the U.K., the improvements in extrapyramidal side effects expected from 2nd-generation antipsychotics has not been realized, while the risk of “life-shortening metabolic disturbances” from 2nd-generation is real enough to warrant a place for the use of 1st-generation antipsychotics; a prospect with implications for education because “a generation of psychiatrists how has little or no experience with first-generation antipsychotic prescription.” Full text of the study appears online in the British Journal of Psychiatry.

Article → 

Peluso MJ, Lewis SW, Barnes TRE, Jones PB. Extrapyramidal motor side- effects of first- and second-generation antipsychotic drugs. The British Journal of Psychiatry 2012; 200:387-392.

Of further interest:
Replies to the Article (in BJP)

“Second Generation Antipsychotics” and Developing Countries- Sri Lankan Experience

“The article on Extrapyramidal motor side-effects of first- and second -generation antipsychotic drugs (Peluso et al. 2012) has been read with concern.

“First generation antipsychotics had been routinely prescribed all over the world a few decades ago whereas they have been continued to be used in the developing countries such as Sri Lanka until recently.

“As we normally follow the prescribing guidelines such as NICE, FDA, Maudsley Guidelines we are also naturally bound to adhere to the contemporary practice in the west. Even though the original brands of second generation antipsychotics produced in the developed countries are more expensive there are cheap affordable brands coming mainly from India available in countries such as Sri Lanka. Hence clinicians are tempted to prescribe more and more second generation antipsychotics. Even in countries such as Sri Lanka many trainees are not very familiar with using first generation anti-psychotics as the clinicians tend to prescribe second generation anti-psychotics for a variety of clinical conditions.

“Globally it seems that there is a rising tendency of prescribing more and more second generation antipsychotics for other clinical conditions such as anxiety disorders, mood disorders and child psychiatric problems. The increasing tendency of psychotropic usage amongst the very young has also been highlighted and the need for guidelines has been discussed( Gleason et al. 2007). Also the increasing trend in second generation antipsychotic prescription for anxiety disorders has been shown( Comer et al. 2011).

“Clinicians note that a considerable number of patients who received first generation antipsychotics such as Haloperidol, Trifluoperazine needed anticholinergics most of the time in order to counteract the extrapyramidal side effects. If we do studies including a bulk of patients who received high potency first generation antipsychotics such as Haloperidol compared with the second generation antipsychotics the outcome( Extrapyramidal Side Effect Profile) might be different.

“Even though there is an increasing trend in prescribing second generation antipsychotics even in our part of the world it is also interesting to note that some clinicians in countries like Sri Lanka still prefer to prescribe conventional anti psychotics such as Haloperidol, Trifluoperazine, Chlorpromazine for special group of patients like the pregnant and lactating mothers as they seem to be more familiar with their side effect profile and comfortable of using them.

“It is clear that we are going to prescribe more and more psychotropic medication for a variety of psychiatric ailments. The benefits of proper prescribing of psychotropic medication in psychiatry have been addressed (Harrison et al. 2011).

“Another important area note worthy in prescribing psychotropic medication is the necessity to pay attention to “Ethno- Psychopharmacology”. Efficacy and the side effect profile may be different amongst various ethnic groups. Pharmacogenetic variations between Asians and other ethnic groups have been highlighted (Pi and Zhu 2007). We need to be aware of the beneficial effects /advantages of “Second Generation Antipsychotics” such as their mood stabilizing properties, anxiolytic properties etc in addition to antipsychotic properties.

“However it is worthwhile reducing the fears/uncertainties of prescribing “First Generation Antipsychotics” amongst the clinicians by educating them further and perhaps considering revising the existing prescribing guidelines as the general assumption is that there are more side effects(particularly extrapyramidal) with first generation antipsychotics which result in poor compliance etc. Perhaps we need to do more research work comparing more potent first generation antipsychotics which were widely prescribed such as Haoperdol, Trifluoperazine etc. with second generation antipsychotics.”

Extrapyramidal motor side-effects and first generation antipsychotics: Are second generation agents still indicated?

“Peluso et. al report on the differential effect of first generation antipsychotics (FGA’s) versus second generation antipsychotics (SGA’s) in ameliorating or exacerbating extrapyramidal side effects (EPS) in a secondary analysis of the CUtLASS-1 trial data(1). They report their findings as “essentially null” and mention that there is weak evidence for clinically significant differences in emergent or relieved EPS between FGA’s and SGA’s. These findings, although based on a secondary analysis, pose interesting and important challenges for the focus of future research into antipsychotics, but also raise some questions about the interpretation of negative study findings.

“The majority of participants (49%) in the FGA group were prescribed sulpiride, a substituted benzamide that has been demonstrated in a meta- analysis to have a significantly lower propensity to cause EPS compared to other FGA’s (2). It could be argued that it would not be unusual to find little differences in the two groups as the FGA group was biased toward sulpiride selection.

“An a priori odds ratio of 2 and 0.5 was selected as clinically relevant, but no reason is given for this choice. The choice of this cut- off seems arbitrary. The authors conclude that their results are “essentially null” and that these two classes of drugs could be used with equivalence in EPS. Although equivalence is possible, failure to reject the null hypothesis does not imply that the null hypothesis is true or that treatments are equal (3). Failure to reject the null at this effect size means that the null would not be surprising at this particular value (4). However given a power of 78%, this implies a relatively high chance (22%) of a type II error. In some cases even a reduction of 20% in EPS occurrence can be clinically meaningful. The CUtLASS study would be underpowered even if a true effect existed at this effect size. Confidence limits around the EPS outcomes also appear to be wide at a number of time points. Although negative findings in superiority trials are important to report, it should be noted that some may argue that meaningful scientific evidence centres on replicated falsification.

“In turn, the dichotomization of EPS outcome measures instead of using changes in continuous EPS scores over multiple time points in a longitudinal design and analysis strategy could potentially underestimate any treatment effect.

“Nevertheless, these findings raise important points for the design of superiority trials. Given the lack of superior efficacy in symptom relief of most SGA’s, if the presence of EPS has become the sine qua non for treatment switches to SGA’s, would this not highlight the importance of adequately powered trials where the primary outcome would be EPS? In addition in trials where EPS is only a secondary outcome, as is commonplace, that this outcome be adequately powered at well motivated, pre-agreed effect sizes? Although of global importance in the current economic climate, this would be particularly important for the developing world where funding authorities meticulously scrutinize the benefits of more expensive treatments.”

No difference in extrapyramidal side effects between first-generation and second-generation antipsychotics (Evidence-Based Mental Health)

From the conclusion of the above review: “Second-generation antipsychotics (SGAs) became the mainstay of treatment for psychotic disorders after licensure trials suggested they induced fewer extrapyramidal side effects (EPS), and might provide advantages in efficacy and cognition. A growing body of evidence suggests that the advantages observed in some of these trials may have been at least in part due to their design. High-dose haloperidol was a common choice as a first-generation antipsychotic (FGA) comparator, ensuring a high risk of EPS compared to the SGAs. Given that many SGAs cause weight gain and metabolic abnormalities, it is not clear that their risk-benefit balance is superior to that of FGAs for the treatment of psychotic disorders. Pragmatic clinical trials have provided mixed results, but generally have not supported substantial real-world advantages for most SGAs over FGAs.

“Peluso and colleagues reported a secondary analysis of data from CUtLASS-1, a pragmatic clinical trial, to evaluate whether SGAs provided any advantage over FGAs in terms of EPS liability. Trends towards resolution of Parkinsonism and akathisia, and a higher rate of tardive dyskinesia, in the SGA group at 12 weeks became null by 52 weeks. The authors concluded that there was no real-world advantage of SGAs in reducing EPS risk. It is important to note that 22% of patients in the FGA group received adjunctive anticholinergic medication, compared with only one in the SGA group. Cognitive outcomes were not measured, so it is unclear as to whether the anticholinergic drugs had any adverse cognitive effects. Quality of life was similar, so the clinical significance of any differences is questionable.

“This study adds to the evidence that many SGAs have no real-world advantage over their FGA counterparts. The story is far from over, but it appears possible that the last 15-plus years of antipsychotic market dominance by SGAs, and massive associated expense, may have done little to improve schizophrenia outcomes. It may in fact have caused more harm than help due to metabolic problems induced by SGAs. It is imperative that the new generations of psychiatrists become familiar with the larger array of antipsychotic options and consider FGAs as viable treatment options for their patients.”

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Kermit Cole
Kermit Cole, MFT, founding editor of Mad in America, works in Santa Fe, New Mexico as a couples and family therapist. Inspired by Open Dialogue, he works as part of a team and consults with couples and families that have members identified as patients. His work in residential treatment — largely with severely traumatized and/or "psychotic" clients — led to an appreciation of the power and beauty of systemic philosophy and practice, as the alternative to the prevailing focus on individual pathology. A former film-maker, he has undergraduate and master's degrees in psychology from Harvard University, as well as an MFT degree from the Council for Relationships in Philadelphia. He is a doctoral candidate with the Taos Institute and the Free University of Brussels. You can reach him at [email protected]


  1. It will take at least another ten years for this to matter. Let’s not forget the second psychiatrist that the boy saw in the PBS documentary The Medicated Child blamed his “tics” on stimulants, even though he wasn’t on them anymore, only because she believed risperdal couldn’t cause movement disorders. I’ll bet that it’s at least another ten years before doctors start admitting this to each other, and another 20 before the public realizes it.

  2. But let me get this straight. The proposed solution to this problem is to just go back to prescribing the old ones? Would we ever have given a million+ kids some haldol or mellaril? Would society ever had allowed doctors to prescribe thorazine for depression? If the second generation is no better than the first, and history has clearly shown that the first generation was terrible, why even think of going back to the first generation?

    • And even when you put this stuff right in front of their eye’s they still go on about how biased the research design for that study was and that they know for fact that second generation are a thousand times better!!

      And of course they have pin up boys as I like to refer to a former next door neighbour. He was put on haldal at the age of 19 when he suffered a psychotic break. At excessively high doses in which he was incontinent and could not walk or talk. He simply lay in bed all day every day. 4 weeks later they deemed him as cured and released him from hospital to return to a 60 hour a week job, no tapering of medications, just cold turkey withdrawl. When he could not cope and who could, they then had “proof” that he had schizophrenia and he would need to be on medication for life!! Sad part is that him and his family have believed it for 40 odd years. He was put back on the excessively high dose of haldal and released to his family. Where he layed on plastic on the couch, day in day out. They had to spoon feed him. The best they could hope for was a better treatment and Resperidone did that. He was one of the first in Australia to be prescribed it. He was put on a very low dose and magically recovered the ability to walk, talk, etc. He does now have heart disease, diabetes, and a mirade of other health problems, but he apparently would not be alive without his Resperidone!! I have handed him copies of the World Health Organisation research about Schizophrenia outcomes in third world countries to be told they are biased researchers and in it for the money. The ONLY people who can be trusted in the research of this stuff is drug companies. I asked if they are biased by money, to which he responded no. It would appear as though the drugs have caused him to become brain dead. But then again the whole family has done the same thing.

      Unfortunately some people will simply believe anything at all. They NEED to believe that these things are brain diseases is I think the only way to describe it.