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2. Node 2 Unsatisfactory Response to an Adequate Antipsychotic Trial
David N. Osser, MD
Associate Professor of Psychiatry
Harvard Medical School
Brockton Division of the VA Boston Healthcare System
General Editor - Psychopharmacology Algorithm Project
Harvard South Shore Residency Training Program

3. FGA (haloperidol, perphenazine)
Node 2:
Risperidone
Olanzapine
FGA (haloperidol, perphenazine)
So our recommendation for Node 2 is that you pick one of the more effective antipsychotics. There are two sets of antipsychotics really out there. I’ll talk a bit about that.
But the more effective ones are risperidone, olanzapine and the first-generation antipsychotics actually, drugs like haloperidol and perphenazine. Those are a little more effective than the others.

4. Greater emphasis on efficacy
Node 2:
Risperidone
Olanzapine
FGA (haloperidol, perphenazine)
Greater emphasis on efficacy
And now, that you’ve tried one, perhaps one of the somewhat less effective ones but you were picking it because you wanted to give the patient a chance to have a side effect profile with their antipsychotic that they could live with more easily over the long term but having tried that and not gotten anywhere with it, now efficacy is a greater consideration and you should pick one of these three choices.

5. Greater emphasis on efficacy
Node 2:
Risperidone
Olanzapine
FGA (haloperidol, perphenazine)
Greater emphasis on efficacy
Now, it may be that you actually did try risperidone the first shot which is actually one of our three more effective medications. So if you did that, you have tried one of our best.
If already tried one of these

6. Greater emphasis on efficacy
Node 2:
Risperidone
Olanzapine
FGA (haloperidol, perphenazine)
Greater emphasis on efficacy
And for the second trial, we say you could try anything you want, any second or first generation that you didn’t try in the first try. We have no preference if you already tried one of the top efficacy antipsychotics, i.e. risperidone.
If already tried one of these
Try any SGA or FGA not tried at node 1

7. Evidence considerations

8. Meta-analyses of industry-sponsored trials
Now, to just review the evidence for that recommendation briefly, meta-analyses of the – primarily, industry-sponsored studies of antipsychotics find no net differences in efficacy. And you’ll hear this a lot. They’re all the same. There’s no advantage to one over the other in their efficacy when you compare these industry-sponsored trials.
No differences in efficacy among antipsychotics
Study populations are atypical
Clean
Little or no comorbidities
Unrepresentative of “real world” situations

9. Meta-analyses of industry-sponsored trials
But these populations treated in the industry-sponsored trials are actually pretty atypical.
No differences in efficacy among antipsychotics
Study populations are atypical
Clean
Little or no comorbidities
Unrepresentative of “real world” situations

10. Meta-analyses of industry-sponsored trials
They’re clean. They have little or no comorbidity of any kind, medical or otherwise. They’re very cooperative, nice patients who will do rating scales, come in for their meetings with you. They’re unrepresentative really of a lot of the real world situations where we encounter our schizophrenia patients. And maybe they don’t capture more subtle differences in the effectiveness of antipsychotics that many clinicians believe exist in the real world.
No differences in efficacy among antipsychotics
Study populations are atypical
Clean
Little or no comorbidities
Unrepresentative of “real world” situations

11. Important differences in the acute inpatient setting
“Real-world” study (Mc Cue et al)
5 SGAs, haloperidol: inpatient setting
Open label trial
Measured whether patients were able to be discharged within 3 weeks
3 antipsychotics did better
Olanzapine (mean dose 19 mg)
Haloperidol (mean dose 16 mg)
Risperidone (mean dose 5.2 mg)
Important differences in the acute inpatient setting
And so we turn to some of those studies done in more real world populations to see if we could detect differences. And indeed, we did. An excellent example of that is a large open label trial conducted by Mc Cue and colleagues where they compared five second-generation antipsychotics and haloperidol in an inpatient setting.
McCUE, R. E., Waheed, R., Urcuyo, L., Orendain, G., Joseph, M. D., Charles, R., & Hasan, S. M. (2006). Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. The British Journal of Psychiatry, 189(5),

12. Important differences in the acute inpatient setting
“Real-world” study (Mc Cue et al)
5 SGAs, haloperidol: inpatient setting
Open label trial
Measured whether patients were able to be discharged within 3 weeks
3 antipsychotics did better
Olanzapine (mean dose 19 mg)
Haloperidol (mean dose 16 mg)
Risperidone (mean dose 5.2 mg)
Important differences in the acute inpatient setting
This was a real world study because it was open label for one thing. People knew what they were giving.
McCUE, R. E., Waheed, R., Urcuyo, L., Orendain, G., Joseph, M. D., Charles, R., & Hasan, S. M. (2006). Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. The British Journal of Psychiatry, 189(5),

13. Important differences in the acute inpatient setting
“Real-world” study (Mc Cue et al)
5 SGAs, haloperidol: inpatient setting
Open label trial
Measured whether patients were able to be discharged within 3 weeks
3 antipsychotics did better
Olanzapine (mean dose 19 mg)
Haloperidol (mean dose 16 mg)
Risperidone (mean dose 5.2 mg)
Important differences in the acute inpatient setting
And the outcome criterion was a very important one for the real world. It was “how quickly are you able to discharge these patients or specifically what was the percent they could be discharged within three weeks?” That was the primary outcome measure rather than the usual rating scale measures that the drug company studies do.
McCUE, R. E., Waheed, R., Urcuyo, L., Orendain, G., Joseph, M. D., Charles, R., & Hasan, S. M. (2006). Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. The British Journal of Psychiatry, 189(5),

14. Important differences in the acute inpatient setting
“Real-world” study (Mc Cue et al)
5 SGAs, haloperidol: inpatient setting
Open label trial
Measured whether patients were able to be discharged within 3 weeks
3 antipsychotics did better
Olanzapine (mean dose 19 mg)
Haloperidol (mean dose 16 mg)
Risperidone (mean dose 5.2 mg)
Important differences in the acute inpatient setting
So they found rather impressive differences in outcome among the six treatments. There were three that were tied. So the three that were tied were olanzapine at a mean dose of 19 mg, haloperidol at a mean dose of 16 and risperidone at a mean dose of 5.
McCUE, R. E., Waheed, R., Urcuyo, L., Orendain, G., Joseph, M. D., Charles, R., & Hasan, S. M. (2006). Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. The British Journal of Psychiatry, 189(5),

15. Important differences in the acute inpatient setting
“Real-world” study (Mc Cue et al)
5 SGAs, haloperidol: inpatient setting
Open label trial
Measured whether patients were able to be discharged within 3 weeks
3 antipsychotics did better
Olanzapine (mean dose 19 mg)
Haloperidol (mean dose 16 mg)
Risperidone (mean dose 5.2 mg)
Important differences in the acute inpatient setting
So this suggests there may be important differences in the effectiveness of antipsychotics in the acute inpatient setting.
McCUE, R. E., Waheed, R., Urcuyo, L., Orendain, G., Joseph, M. D., Charles, R., & Hasan, S. M. (2006). Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. The British Journal of Psychiatry, 189(5),

16. Primarily industry-sponsored trials Similar trend
Meta-analysis
Primarily industry-sponsored trials
Similar trend
Except for haloperidol finding
Effectiveness trials
Risperidone and olanzapine better
Quetiapine less effective in acute setting
Cochrane review
Ziprasidone less effective
And they are actually consistent with another meta-analysis by Leucht and colleagues also of primarily industry-sponsored trials but looking at other of the outcome measures that they used. They also found somewhat of the same trend. And Haldol though was the one exception. Leucht didn’t find Haldol to be as good in their meta-analysis as the Mc Cue and colleagues did in their study.
Leucht, S., Corves, C., Arbter, D., Engel, R. R., Li, C., & Davis, J. M. (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. The Lancet, 373(9657),

17. Primarily industry-sponsored trials Similar trend
Meta-analysis
Primarily industry-sponsored trials
Similar trend
Except for haloperidol finding
Effectiveness trials
Risperidone and olanzapine better
Quetiapine less effective in acute setting
Cochrane review
Ziprasidone less effective
There are three other effectiveness trials that found risperidone and olanzapine better, and quetiapine less effective in acute settings.
Suzuki, T., Uchida, H., Watanabe, K., Nomura, K., Takeuchi, H., Tomita, M., ... & Tanabe, A. (2007). How effective is it to sequentially switch among Olanzapine, Quetiapine and Risperidone?—A randomized, open-label study of algorithm-based antipsychotic treatment to patients with symptomatic schizophrenia in the real-world clinical setting. Psychopharmacology, 195(2),

18. Primarily industry-sponsored trials Similar trend
Meta-analysis
Primarily industry-sponsored trials
Similar trend
Except for haloperidol finding
Effectiveness trials
Risperidone and olanzapine better
Quetiapine less effective in acute setting
Cochrane review
Ziprasidone less effective
And a Cochrane review, I’ve already mentioned it before, of ziprasidone found that less effective.
Komossa K, Rummel-Kluge C, Schmid F, et al.(2009) Aripiprazole versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev

19. Meta-analysis Efficacy hierarchy 212 RCTs More than 43,000 patients
Clozapine
Amisulpride
Olanzapine
Risperidone
Paliperidone
Zotepine
Haloperidol
Quetiapine
Aripiprazole
Asenapine
Lurasidone
Iloperidone
And there’s another meta-analysis again by Leucht. . So he looked at 212 randomized trials of antipsychotics where you could detect potential differences involving more than 43,000 patients.
Meta-analysis
212 RCTs
More than 43,000 patients
Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., ... & Kissling, W. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 382(9896),

20. Meta-analysis Efficacy hierarchy 212 RCTs More than 43,000 patients
Clozapine
Amisulpride
Olanzapine
Risperidone
Paliperidone
Zotepine
Haloperidol
Quetiapine
Aripiprazole
Asenapine
Lurasidone
Iloperidone
They tried to create an efficacy hierarchy and here’s what they found.
Meta-analysis
212 RCTs
More than 43,000 patients
Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., ... & Kissling, W. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 382(9896),

21. Meta-analysis Efficacy hierarchy 212 RCTs More than 43,000 patients
Clozapine
Amisulpride
Olanzapine
Risperidone
Paliperidone
Zotepine
Haloperidol
Quetiapine
Aripiprazole
Asenapine
Lurasidone
Iloperidone
Clozapine was first followed by amisulpride next. See, amisulpride is up there. Olanzapine, risperidone, paliperidone and then down from there, zotepine, haloperidol, quetiapine, aripiprazole, asenapine, lurasidone and iloperidone. So again, it’s consistent with what we’re recommending in our algorithm for what you should pick for your second-line treatment after your first-line choices.
Meta-analysis
212 RCTs
More than 43,000 patients
Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Örey, D., Richter, F., ... & Kissling, W. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 382(9896),

22. Node 2 Recommendations

23. 2nd Antipsychotic
So in summary, our Node 2 recommendations are trying a carefully selected second antipsychotic.

24. FGA Olanzapine Risperidone 2nd Antipsychotic
If you didn’t try it before, use either FGAs, olanzapine or risperidone,

25. Any other antipsychotic except clozapine
FGA
Olanzapine
Risperidone
2nd Antipsychotic
and any antipsychotic other than clozapine though if you did try one of those at first.
Any other antipsychotic except clozapine

26. Olanzapine: prevent weight gain
Lifestyle changes, diet and exercise
Topiramate + olanzapine
Promising study
Metformin
Weight and metabolic parameters
Short-term studies
And if you’re going to pick olanzapine here, we certainly feel like you’ve got to take steps to try to prevent weight gain or even prevent weight gain if possible.

27. Olanzapine: prevent weight gain
Lifestyle changes, diet and exercise
Topiramate + olanzapine
Promising study
Metformin
Weight and metabolic parameters
Short-term studies
You can try to persuade the patient to make the lifestyle changes, diet and exercise, that might mitigate the metabolic side effects. And there are some small subpopulations of schizophrenia patients that really can cooperate with that. I think it’s a very small percentage but certainly you try to do that.

28. Olanzapine: prevent weight gain
Lifestyle changes, diet and exercise
Topiramate + olanzapine
Promising study
Metformin
Weight and metabolic parameters
Short-term studies
There was an interesting randomized trial where they added topiramate to olanzapine at baseline versus adding placebo to olanzapine to see how much weight they gained and what other side effects they developed. Remarkably, the folks who were on topiramate plus olanzapine did not gain any weight. Whereas, those on placebo plus olanzapine had the usual acute weight gain from olanzapine. Very promising study but it really needs replication. And topiramate does have a variety of potentially important side effects. So I don’t think we want to put everybody on topiramate and keep them on it forever, who you’re going to put on olanzapine. But if they’re starting to gain weight quickly on olanzapine, by all means, consider either switching it or possibly it might be helpful to add topiramate.
Narula, P. K., Rehan, H. S., Unni, K. E. S., & Gupta, N. (2010). Topiramate for prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia: a double-blind, placebo-controlled trial. Schizophrenia research, 118(1),

29. Olanzapine: prevent weight gain
Lifestyle changes, diet and exercise
Topiramate + olanzapine
Promising study
Metformin
Weight and metabolic parameters
Short-term studies
Metformin has also had a lot of research as a method for dealing with weight and metabolic parameters associated with drugs like olanzapine. These studies are all short-term but are consistently showing positive results.
There have been a number of editorials after this article saying “gee, you know, maybe we should have this be routine.” No one has gone out on that limb yet and said it should be routine to add metformin to anyone on olanzapine. Metformin actually doesn’t cause that much weight loss. It’s more impressive the way it changes metabolic parameters like measures of treatment resistance, triglyceride levels and so forth than the actual poundage lost.
Klein, D. J., Cottingham, E. M., Sorter, M., Barton, B. A., & Morrison, J. A. (2006). A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. American Journal of Psychiatry, 163(12),
Wu, R. R., Zhao, J. P., Guo, X. F., He, Y. Q., Fang, M. S., Guo, W. B., ... & Li, L. H. (2008). Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. American Journal of Psychiatry, 165(3),

30. Node 2a: Intolerance or Inadequate Trial of Node 2 Antipsychotic

31. Choose another Node 2 antipsychotic
Poorly tolerated AP/unable to give adequate trial?
And we conclude today’s portion of this talk by telling you what’s in Node 2a which is what happens if you couldn’t give an adequate trial of this medication you selected at Node 2 because of toxicity, patient refusal or whatever. So you still haven’t completed Node 2. You didn’t finish an adequate trial on your selected drug.

32. Choose another Node 2 antipsychotic
Poorly tolerated AP/unable to give adequate trial?
Well, we would then suggest choosing another from the recommended options that we just went through for Node 2 so that you will finally by the end of Node 2a at least have completed two adequate trials and you’re ready to consider what to do next. And that will be saved for the next talk.

33. End of Presentation