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Day # 18: Antipsychotic Clinical Pearls

Now that we have covered the side effects of antipsychotic medications, let's take some time to discuss general principles of prescribing, dosing considerations, highlight landmark clinical trials, and strategies to increase adherence.

This is going to be a somewhat random but useful assortment of information that I think is important when prescribing these medications.

Today's Content Level: Intermediate

Important Clinical Trials and Guidelines (CATIE; CUtLASS; NICE)

CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness

CUtLASS = Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study

NICE = National Institute for Health and Care Excellence

•Two important studies regarding antipsychotic medications are the CATIE and CUtLASS trials.

•The basic clinical question in both studies was to compare multiple first-generation antipsychotics (FGA's) and second-generation antipsychotics (SGA's) in terms of relative effectiveness, side effects, and adherence.

•Unfortunately, one of the biggest take home points of these studies is that a minority of patients remain adherent to antipsychotic medications. On average, only 26% of participants completed the 18-month long CATIE trial. 1 The main outcome measure was discontinuation of treatment.

•In regards to treatment efficacy there were few differences between FGA's and SGA's as groups and overall no significant difference overall in efficacy or quality of life. There were minor advantages in treatment response to olanzapine and amisulpride individually (better treatment response and associated with a longer time to discontinuation). However this is balanced with greater weight gain, hyperlipidemia, and hyperglycemia. 2

•FGA's vs SGA's? Studies show that if differences in EPS could be minimised (by careful dosing) and anticholinergic use avoided, there was no convincing evidence to support any advantage for SGA's over FGA's. As a class, SGA's may have a lower propensity to cause EPS and tardive dyskinesia but this is somewhat offset by a higher propensity to cause metabolic adverse effects. 3

•How do SGA's compare? A meta-analysis of these landmark studies and additional research also highlights that differences in treatment efficacy between individual (non-clozapine) SGA's are comparable. A relative ranking of effectiveness of the medications studied is as follows: Olanzapine > Amisulpride > Risperidone > Quetiapine, Ziprasidone. 4 These differences are small but possibly substantial enough to be clinically important. Keep in mind, however, that adherence is most important, so patient's choice is of utmost importance.

•For patients whose symptoms have not responded sufficiently to adequate, sequential trials of two or more antipsychotic drugs, clozapine is clearly the most effective treatment. It is the only antipsychotic that shows a clear advantage in regards to treatment response. Because of significant side effects and other unique aspects of this medication it is typically reserved for treatment resistant cases. The biological basis for the superior efficacy of clozapine is uncertain. We will discuss clozapine in more detail in a few days during a dedicated lesson to clozapine. 5

General Principles of Prescribing

•Antipsychotics are effective in both the acute and maintenance treatment of schizophrenia and other psychotic disorders. They differ in their pharmacology, pharmacokinetics, overall efficacy/effectiveness and tolerability, but perhaps more importantly, response and tolerability differ between patients. This variability of individual response means that there is no clear first‐line antipsychotic medication that is preferable for all.

•As discussed above, most antipsychotic medications are comparable in effectiveness. The most important element of treatment is likely whether they actually take the medications! Per NICE guidelines, patients should be as involved in decisions about the choice of medicines as possible.

•Use the LOWEST dose possible (at least the minimum effective dose). Wait for a treatment response for 1-2 weeks before escalating the dose. Do not keep increasing the dose day after day in the hospital. Lack of response at 2 weeks is a potent predictor of later poor outcome unless the dose or drug is changed. 6

•There is no firm evidence that high doses of antipsychotic medication are any more effective than standard doses for schizophrenia. Despite this, approximately 25-33% of hospitalized patients are on a “high dose” (above 100% of recommended dose) above licensed ranges. Efficacy appears to be optimal at relatively low doses. If high doses are trialed, target symptoms should be assessed after 6 weeks and 3 months and if insufficient improvement in symptoms, the dose should be decreased to the normal range. 7

Combination antipsychotics should be avoided unless absolutely necessary. There is very little evidence to support this practice although it is routinely done. Single antipsychotic (with or without additional mood stabilizer or sedatives) is recommended. An exception is clozapine augmentation. In addition to general side effects, polypharmacy should be avoided due to high risks of QTc prolongation and sudden cardiac death. 8

•Regularly monitor physical health parameters as discussed earlier in this theme.

•Responses to antipsychotic drug treatment should be assessed by recognized rating scales and documented.

•If considering stopping antipsychotics: Is patient free of distressing symptoms? How severe are the side effects? What happened when previous dose reduction was attempted? Does the patient have a stable social situation? Is the patient able to seek help?

Non-adherence is common. In comparison with oral antipsychotics, there is strong evidence that long-acting injectable (LAI) depots are associated with a reduced risk of relapse and re-hospitalization. You should always try to use a "test dose" of the oral medication first to test for tolerability before giving the injectable version. Commonly used LAI include aripiprazole, paliperidone, haloperidol, risperidone, and olanzapine. 9

•General treatment algorithm:

  • Choose antipsychotic with patient (lean towards SGA) -> Titrate to minimum effective dose -> Assess over two weeks -> continue if effective.

  • If not effective after 2 weeks -> Increase dose. -> If not effective after increasing dose -> switch medication (consider olanzapine due to slight increased effectiveness) and follow above. If not effective after two full med trials -> switch to clozapine.

  • Maximize psychosocial factors, therapy, and family involvement. See this post for more details.

  • Switch to LAI as soon as possible once tolerability is obtained if LAI option.


I hope you found today's article helpful. Tune in tomorrow for a discussion about switching antipsychotics, treatment-resistant schizophrenia, and more information about clozapine.

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