First vs second generation agents in schizophrenia

[Asterix]

I have heard that first generation drugs are less effective than 2nd generation, is this true though, the articles I have read state there is no difference on the outcome of health.

[Nikolai]

Interestingly the 2009 NICE guidelines do not stress an atypical being first line - "oral antipsychotics should be offered" taking into account benefits/risk, EPS, metabolic effects, etc. However most prescribers these days would still go for an atypical first line, unless they are part of the minority of old hardcore prescribers who were used to prescribing chlorpromazine and others 40-50 years ago. Typicals are more likely to give acute EPS, sedation, anthistamine and antimuscarinic effects (all depending on drug) as well as there being a long term risk of TD. Generally the older drugs are probably as efficacious as the newer drugs, although a couple of studies suggest olanzapine, amisulpride and risperidone are mroe efficacious. Probably the major difference between the 2 groups is the size of the therapeutic index relative to acute EPS, e.g olanzapine has a wider index (20-40mg/day) c.f. haloperidol (prob<0.5mg/day).

[Asterix]

do you have any links to these newer studies

[Nikolai]

Davis JM et al. A meta-analysis of the efficacy of second-generation antipsychotics. Archives of General Psychiatry 2003; 60:553–564.

See p7 efficacy differences

Leucht S et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31–41.

Again look at overall efficacy and discussion

[bobbin]

I have heard that first generation drugs are less effective than 2nd generation, is this true though, the articles I have read state there is no difference on the outcome of health.

This is not an easy question to answer. Response to antipsychotic drugs is extremely variable from patient to patient. Some patients will respond best to low doses, others will need high doses, some will have severe side effects - some won't, some will respond well to one drug but will get worse when prescribed another etc. Because of this, it is important that a large variety of antipsychotics remain available.

The '2nd generation' drugs are quite variable. Some may be more effective than others and side effects can differ considerably. Overall, clozapine (Clozaril) seems to be the most effective, possibly followed by olanzapine (Zyprexa). Clozapine and olanzapine can both cause profound weight gain and metabolic adverse effects. These two drugs do tend to be more effective than 1st generation drugs, but cause considerably more obesity whilst causing fewer movement disorders.

Out of the 1st generation drugs, haloperidol has been frequently compared to the newer drugs. Unfortunately, these studies have always used very high doses of haloperidol - which can cause severe side effects. If the studies had used lower, more reasonable doses of haloperidol, the results may have been different. Haloperidol is an exceptionally potent neuroleptic and there is no excuse for using massive doses.

A recent study called CATIE compared perphenazine (a mid-potency 1st generation drug) with a variety of newer drugs. Perphenazine was chosen instead of haloperidol because haloperidol is so potent that small increases in dose may lead to abrupt increases in side effects. Being less potent, perphenazine is easier to use.

The results showed that perphenazine was similar to efficacy to risperidone and quetiapine (Seroquel). Olanzapine was more effective but caused so much weight gain that many patients had to stop taking it.

Unexpectedly, movement disorders were not seen more frequently with perphenazine. This is probably because the study used relatively low (sensible) doses of perphenazine.

Here is Bobbin's Summary of antipsychotics when used in schizophrenia..........

Clozapine (Clozaril) - High efficacy but causes considerable sedation and weight gain. Needs regular blood tests. Widely used by psychiatrists for severe, resistant schizophrenia. Low risk of movement disorders.

Olanzapine (Zyprexa) - Moderately high efficacy. Sedation and weight gain very common. Movement disorders less common than with most antipsychotics except clozapine.

Quetiapine (Seroquel) - Moderate efficacy, probably similar to first generation drugs. Sedation very common and moderate weight gain. Movement disorders uncommon, similar in frequently to clozapine.

Risperidone (Risperdal) - Moderate efficacy, possibly slightly more effective than most first generation drugs. Relatively low sedation and moderate weight gain. Movement disorders uncommon at low doses but very common at high doses.

Amisulpride (Solian) - Moderate efficacy, possibly slightly more effective than most first generation drugs. Low sedation and modest weight gain. Movement disorders relatively common but considerably milder than haloperidol. Very similar drug to sulpiride (Dolmatil).

Aripiprazole (Abilify) - One of the newest antipsychotics. Moderate efficacy, possibly slightly more effective than most first generation drugs. Low sedation and weight gain. Moderate risk of movement disorders but often causes restlessness.

Haloperidol (Serenace, Haldol) - 1st generation drug. Moderate efficacy. High risk of movement disorders, especially if the dose is excessive. Some patients may do well on very low doses with considerably fewer side effects. Haloperidol is not very sedating and weight gain is not generally marked. Haloperidol often causes restlessness (akathisia). Haloperidol is a very potent drug and the dose needs to be titrated with care. Newly diagnosed patients normally require low doses.

Perphenazine - 1st generation drug. Moderate efficacy. Movement disorders are common but less so if the dose is kept low. Sedation and weight gain are minor.

Chlorpromazine - 1st generation drug. Moderate efficacy. Movement disorders are usually mild at low doses but common at high doses. Sedation and weight gain are frequent. Weight gain is less severe than with olanzapine and clozapine, however!

Depot neuroleptics eg. Clopixol Depot - Moderate efficacy, may improve efficacy for those who do not take their tablets. Extremely high risk of movement disorders, which can be severe, particularly shortly after the injection. Newer depots such as Risperdal Consta and Zypadhera are different. For example, Zypadhera is much more sedating but causes milder movement disorders.

[Nikolai]

Don't forget CUtLass - Primary outcome was quality of life, where the authors concluded 2nd generation drugs showed no advantaged over the 1st generation drugs at 1 year, and actually that the latter group fared better. Problem is that both trials looked at first generation drugs which are not as commonly prescribed. However saying that, both groups are prob as efficacious and the ultimate decision as to what to prescribe is based on the patient as a whole.

[bobbin]

Don't forget CUtLass - Primary outcome was quality of life, where the authors concluded 2nd generation drugs showed no advantaged over the 1st generation drugs at 1 year, and actually that the latter group fared better. Problem is that both trials looked at first generation drugs which are not as commonly prescribed. However saying that, both groups are prob as efficacious and the ultimate decision as to what to prescribe is based on the patient as a whole.

In my opinion, the efficacy of the SGAs compared with the FGAs has been overexaggerated. The SGAs are very expensive and have generated absolutely vast profits for the manufacturers. I do believe that the SGAs have a definite place in treatment, however. Fortunately, we now have inexpensive generic versions of some of the earlier SGAs such as risperidone. The risk of tardive dyskinesia remains a particular concern with the FGAs.

As far as I know, CUtLASS classified sulpiride as a FGA......and it was widely used in the study. This is not entirely reasonable since sulpiride is very similar to amisulpride, which is classed as a SGA.