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Optimizing Pharmacologic Treatment of Psychotic Disorders MEDICATION SELECTION, DOSING, AND DOSEEQUIVALENCE Guideline 1: Selecting Initial Pharmacologic Treatment 1A. First-Episode Patient
For a first-episode patient with predominantly positive symptoms, the experts consider oral risperidone the treatment of
choice. Other recommended medications for this clinical situation are aripiprazole, olanzapine, ziprasidone, and queti-
apine (although the first two were rated first line and the second two high second line, these options clustered together
and all were rated first line by approximately two-thirds of the experts).
For a first-episode patient with predominantly negative symptoms, the experts recommend one of the newer oral atypi-
cal antipsychotics. Risperidone and aripiprazole received first line ratings, and the other three were rated high second
line; however, all the options clustered together with only small differences in their confidence intervals.
For a first-episode patient with both prominent positive and negative symptoms, the experts prefer oral risperidone.
Other recommended medications for this clinical situation are aripiprazole, ziprasidone, olanzapine, and quetiapine
(again these four options clustered together with only small differences in their confidence intervals).
The experts as a group varied in their ratings of using a long-acting injectable atypical antipsychotic for a first-episodepatient to such an extent that there was no consensus on this item (with approximately a quarter of the experts rating itfirst line and approximately a third giving it third line ratings). The experts did not recommend the use of either oral ordepot conventional antipsychotics for a first-episode patient (conventional antipsychotics received third line ratings inevery case).
(bold italics = treatment of choice)
Presentation
First Line*
High Second Line
Other Second Line
Predominantly positive
Risperidone
Predominantly negative
*In this survey, we asked only about oral and long-acting injectable formulations of antipsychotics. Unless otherwise specified, allmedications listed in the tables refer to the oral formulation.
†At the time of this survey, a long-acting injectable atypical antipsychotic was not available in the United States, although it wasavailable in several other countries. In the survey, we asked the experts to rate how they would use such a formulation if it wereavailable.
1B. Multi-Episode Patient
For a multi-episode patient with predominantly positive symptoms, the experts consider oral risperidone the treatment
of choice. Other recommended first line medications for this clinical situation are aripiprazole, ziprasidone, olanzapine,
and quetiapine and a long-acting atypical antipsychotic. Clozapine was rated high second line. Other lower rated second
line options were a long-acting conventional antipsychotic (depot) and an oral high-potency conventional.
For a multi-episode patient with predominantly negative symptoms, risperidone, aripiprazole, and ziprasidone were
rated first line; high second line choices were olanzapine, quetiapine, a long-acting atypical antipsychotic, and clozapine.
(It should be noted that all these options tended to cluster together, with only small differences in their confidence inter-
vals.) A long-acting conventional antipsychotic was a lower rated second line option.
For a multi-episode patient with both prominent positive and negative symptoms, the experts preferred risperidone
followed by aripiprazole. Other first line options were ziprasidone and olanzapine. High second line choices were a long-
acting atypical antipsychotic, quetiapine, and clozapine. (Ratings for most of these options tended to cluster together
with only small differences in their confidence intervals.) Other lower rated second line options were a long-acting depot
conventional antipsychotic and an oral high-potency conventional.
The experts are clearly more willing to consider using clozapine or a long-acting injectable antipsychotic in a patientwith a history of previous psychotic episodes. The experts did not recommend the use of mid- or low-potency conven-tional antipsychotics and gave only very limited support to the use of oral high-potency conventionals.
(bold italics = treatment of choice)
Presentation
First Line
High Second Line
Other Second Line
Predominantly positive
Risperidone
Predominantly negative
Optimizing Pharmacologic Treatment of Psychotic Disorders Guideline 2: Adequate Dose of AntipsychoticsQuestions 4 & 6We asked the experts to write-in doses of conventional and atypical antipsychotics that they would recommend in differ-ent treatment situations. We used the mean and standard deviations of their responses to generate real-world dosesrounded to currently available pill strengths. The experts’ dosing recommendations generally agree closely with recom-mended doses given in the package labeling. For olanzapine and quetiapine, their recommendations for highest acutedose are somewhat higher than the highest doses for which safety data from clinical trials are available (20 mg of olan-zapine and 800 mg of quetiapine). The panel would generally use higher doses for a patient who had had multiple epi-sodes of psychosis than for a first-episode patient. The recommended dose ranges for maintenance treatment are alsoslightly lower than for acute treatment.
First-episode patient
Multi-episode patient
Maintenance
Maintenance
Highest final
treatment
treatment
treatment
treatment
acute dose
Medication
(mg/day)*
(mg/day)
(mg/day)*
(mg/day)
(mg/day)
Atypicals
Conventionals
*In beginning treatment with an oral antipsychotic for which titration is not required or with a long-acting injectable antipsychotic, theexperts recommend either starting with a low dose and increasing the dose based on level of response and side effects, or starting witha moderate dose. The experts do not recommend starting with a relatively high dose and then decreasing it if possible.Questions 10 & 11 †Safety of doses of olanzapine > 20 mg/day and of quetiapine > 800 mg/day have not been evaluated in clinical trials.
‡The package labeling for thioridazine includes a black box warning stating that this agent “has been shown to prolong the QTcinterval in a dose related manner, and drugs with this potential, including thioridazine, have been associated with torsades de pointes-type arrhythmias and sudden death. Due to its potential for significant, possibly life-threatening, proarrhythmic effects, thioridazineshould be reserved for use in the treatment of schizophrenic patients who fail to show an acceptable response to adequate courses oftreatment with other antipsychotic drugs.” Guideline 3: Therapeutic Drug Monitoring (Using Plasma Levels)Question 5Over 50% of the experts reported that plasma level assays were available to them only for clozapine, haloperidol, andhaloperidol decanoate. Clozapine was the agent for which the experts considered plasma levels most clinically useful.
Over half the experts use plasma levels of clozapine and haloperidol to monitor compliance; 88% of the experts useclozapine levels to adjust dose, primarily if there has been an inadequate response or side effects are a problem. 50% ofthe experts use plasma levels of haloperidol (oral or decanoate) to adjust dose levels if the patient has an inadequateresponse or problematic side effects.
Guideline 4: Duration of an Adequate TrialQuestion 13If a patient is having little or no response to the initial or to the second antipsychotic that is tried, the experts recommendwaiting a minimum of 3 weeks and a maximum of 6 weeks before making a major change in treatment regimen. If thepatient is showing a partial response to treatment, the experts would extend the duration of the trial somewhat, waiting4–10 weeks before making a change for the initial antipsychotic and 5–11 weeks for the second antipsychotic. A majorchange in treatment regimen could mean either a significant dose increase or switching to a different agent. Note that theexperts would wait longer if the patient is having a partial response, especially in the second trial. Although the differ-ences were not dramatic, they are interesting, particularly given the lack of data from controlled trials addressing theseissues. These results are similar to those from the 1996 Expert Consensus Guidelines on the Treatment of Schizophre-nia,* which recommended waiting 3–8 weeks if there is no response and 5–12 weeks if there is a partial response beforeswitching to another pharmacologic strategy.
4A. Inadequate Response to Initial Antipsychotic Minimum number of
Maximum number of
weeks to wait
weeks to wait
4B. Inadequate Response to Second Antipsychotic Minimum number of
Maximum number of
weeks to wait
weeks to wait
* McEvoy JP, Weiden PJ, Smith TE, et al. The expert consensus guideline series: treatment of schizophrenia. J Clin Psychiatry1996;57(suppl 12b):1–58 Optimizing Pharmacologic Treatment of Psychotic Disorders 5A. To HaloperidolQuestion 7We asked the experts to write-in doses of conventional and atypical antipsychotics that they would consider equivalentto a range of haloperidol doses. We used the mean and standard deviations of their responses to generate real-worlddoses rounded to currently available pill strengths. The goal was to obtain a better sense of the equivalency between theolder conventional antipsychotics and the new generation of atypical antipsychotics. In general, the experts’ responsesfollowed a very linear pattern, indicating that it would probably be possible to use linear formulas to calculate doseequivalency. It is interesting to note that, in every case, the dose the experts consider equivalent to 30 mg of haloperidolis higher than the highest acute dose the experts indicated they would usually use (see Guideline 2).
Haloperidol
Atypicals
Conventionals
*For fluphenazine decanoate and haloperidol decanoate, the experts were asked to indicate the dosage they consider equivalent to thatdose of oral haloperidol being given daily on an ongoing basis.
5B. To RisperidoneQuestion 8We asked the experts to write-in doses of conventional and atypical antipsychotics that they would consider equivalentto a range of risperidone doses. We used the mean ± the standard deviation of their responses to generate real-worlddoses rounded to currently available pill strengths. The goal here was to obtain a better sense of the equivalency of dosesamong the new generation of atypical antipsychotics. Again, the experts’ responses generally followed a very linearpattern, indicating that it would probably be possible to use linear formulas to calculate dose equivalency. It is interestingto note that the doses the experts consider equivalent to 10 mg of risperidone are closest to those they consider equiva-lent to 20 mg of haloperidol (as would be expected since they indicated that they considered 10.5 mg of risperidone to beequivalent to 20 mg of haloperidol, see Guideline 5A).
Risperidone
Atypicals
Conventionals
*For fluphenazine decanoate and haloperidol decanoate, the experts were asked to indicate the dosage that they consider equivalent tothat dose of oral risperidone being given daily on an ongoing basis.
Optimizing Pharmacologic Treatment of Psychotic Disorders 6A. Factors to Consider in Dose AdjustmentQuestion 9The experts considered the use of concomitant medications, the patient’s age, and the presence of hepatic disease themost important factors to consider in adjusting the acute antipsychotic dose. The priority given to the use of concomitantmedications reflects our expanding knowledge of drug-drug interactions and their potential consequences. Other impor-tant factors to consider are the presence of cardiovascular or renal disease, whether or not the patient smokes, and thepatient’s weight. There was no consensus about the importance of the patient’s sex, with 30% of the experts saying theywould nearly always consider the patient’s sex in dose adjustment and 23% saying they would rarely or never considerit. It is surprising that many of the experts (45%) would only sometimes consider the patient’s weight in adjusting thedose. This is consistent with the observation that the determination of psychiatric drug dosage is infrequently influencedby the patient’s weight, despite the fact that (given the highly lipophilic nature of these compounds) blood levels mayultimately be influenced by body mass. It may also reflect the pharmaceutical industry’s desire to simplify dosage de-termination in the treatment of psychiatric disorders.
Always consider
Sometimes consider
6B. Dose Selection for Special PopulationsQuestion 12
Dose Selection for Children and Adolescents. A majority of the experts would not generally use the following medica-
tions in children with a psychotic disorder who are 12 years of age or younger: aripiprazole, clozapine, chlorpromazine,
fluphenazine, perphenazine, thioridazine, thiothixene, trifluoperazine, fluphenazine decanoate, and haloperidol de-
canoate. A majority of the experts would not generally use the following medications in an adolescent (13–18 years old)
with a psychotic disorder: chlorpromazine, perphenazine, thioridazine, thiothixene, trifluoperazine. The doses recom-
mended for pediatric patients are generally much lower than those given for adult patients (see Guideline 2), while the
doses recommended for adolescents are only somewhat lower than those recommended for adults. These results under-
score the need for more data on optimum dosing for children and adolescents.
Dose Selection for Elderly Patients. The experts generally recommend using lower doses in elderly patients than in
younger adults. This probably reflects concerns about slower metabolism and greater sensitivity to adverse effects in
older patients. Older patients are also more likely to have comorbid medical conditions and to be taking multiple medi-
cations, increasing the risk for adverse effects and drug-drug interactions. The experts generally recommend using much
lower doses in elderly patients with dementia than in those with a psychotic disorder. The majority of the experts would
not generally use the following medications in an elderly patient with a psychotic disorder or with dementia: chlorpro-
mazine, thioridazine, thiothixene, trifluoperazine; 70% would also avoid haloperidol or fluphenazine decanoate in eld-
erly patients with dementia.
Elderly Patients with
Children with a
Adolescents with a
Psychotic
Dementia with behavioral
Medication
psychotic disorder
psychotic disorder
disorder
disturbance and/or psychosis
Atypicals
Conventionals
*A majority of the experts would not generally use this medication in this population.
†Although with current formulations it would be difficult to administer 15 mg of haloperidol decanoate, this low mean suggests thatthe experts would be very cautious in dosing if it is decided to use this medication in children or elderly patients with dementia.
Optimizing Pharmacologic Treatment of Psychotic Disorders Guideline 7: Strategies When There Is an Inadequate Response 7A. When to Switch AntipsychoticsQuestion 14For each antipsychotic, we asked the experts whether they would increase the dose or switch to another agent if a multi-episode patient was having an inadequate response to the average target dose of the medication (see Guideline 2 forrecommended target doses). Over 90% of the experts would first increase the dose of clozapine and olanzapine beforeswitching, going as high as 850 mg/day of clozapine and 40 mg/day of olanzapine. Over 80% would increase the dose ofquetiapine and risperidone before switching, going as high as 1100 mg/day of quetiapine and 10 mg/day of risperidone.
Approximately 60% or more of the experts would also increase the dose of aripiprazole, ziprasidone, and the decanoateformulations of fluphenazine and haloperidol. The experts are divided fairly evenly as to whether increasing the dose orswitching is the best strategy if a patient is having an inadequate response to the recommended target dose of one of theconventional oral antipsychotics, except for thioridazine, where 67% would switch to another agent. The experts may beless willing to increase the dose of the conventional oral medications because of concern about side effects, especiallyEPS and TD, at higher doses.
Inadequate response
to adequate dose of
Strategy
Atypicals
Increase dose
Target dose
Switch medications
(% of experts)
(mg/day)
(% of experts)
Conventionals
7B. Switching Antipsychotics: Selecting the Next AgentQuestion 15We asked the experts to indicate the first and second antipsychotics they would try after an inadequate response to theinitial medication. The table lists those agents written in by 10% or more of the experts in Question 15. Note that, aftertrials of two atypical antipsychotics, 30% or more of the experts would switch to clozapine; this was recommended as afirst line strategy in this situation by 70% of the experts in Question 18. The discrepancy between the responses inQuestions 15 and 18 probably reflects differences in the way the question was posed as well as lack of certainty in thefield as to the most appropriate place for clozapine in the treatment algorithm. The editors would endorse the responsegiven in question 18, where approximately three quarters of the experts recommend switching to clozapine after inade-quate response to two atypical antipsychotics (see Guideline 7G). For patients who had started with a conventionalantipsychotic, the experts are more likely to try two other atypical antipsychotics before moving on to clozapine.
First medication you
Second medication you would
Inadequate response to:
would switch to*
switch to
Optimizing Pharmacologic Treatment of Psychotic Disorders First medication you
Second medication you would
Inadequate response to:
would switch to*
switch to
*If the patient did not respond to the initial antipsychotic you tried and you have switched to another antipsychotic, the experts recom-mend waiting 3–6 weeks before making a major change in treatment regimen (e.g., switching to yet another antipsychotic) if the patient ishaving little or no response to treatment, and waiting 5–11 weeks if the patient is having a partial response to treatment.Question 13 7C. Switching Antipsychotics: Target DosesQuestion 15The recommended target doses for the second and third antipsychotics the experts would try are, for the most part,consistent with the acute target doses shown in Guideline 2, although there is a tendency to consider using doses at thehigher end of the range, especially for the third medication tried.
Dosing of first switch
Dosing of second switch
(mg/day)
(mg/day)
Atypicals
Conventionals
Optimizing Pharmacologic Treatment of Psychotic Disorders 7D. Preferred Switching Strategies for Oral AntipsychoticsQuestion 16We asked the experts what strategy they would use in switching to each of the oral atypical antipsychotics, assuming thatthe first antipsychotic does not require tapering before discontinuation. In switching to any of the oral atypicals exceptclozapine, the experts recommend using cross-titration (gradually tapering the dose of the first antipsychotic whilegradually increasing the dose of the second) or overlap and taper (continuing the same dose of the first antipsychoticwhile gradually increasing the second to a therapeutic level and then tapering the first). For each drug, a larger percent-age of the experts considered cross-titration first line. In switching to clozapine, the experts recommend using cross-titration, probably reflecting the need to institute clozapine treatment gradually and not to withdraw the previous medi-cation abruptly or prematurely. They would also consider using overlap and taper in switching to clozapine (rated highsecond line). The experts do not recommend strategies that involve stopping the first antipsychotic before beginning thesecond.
When switching to:
First Line
High Second Line
7E. Preferred Switching Strategies for Injectable AntipsychoticsQuestion 17In switching to a depot conventional antipsychotic, the experts recommend either continuing the oral antipsychotic at thesame dose until therapeutic drug levels of the injectable antipsychotic are achieved and then gradually tapering the oralantipsychotic or else beginning to taper the oral antipsychotic gradually after giving the first injection, with a largerpercentage of the experts favoring the first strategy. Some experts would consider discontinuing the oral antipsychoticimmediately once therapeutic levels of the injectable antipsychotic are achieved.
The experts’ recommendations for switching to a long-acting atypical antipsychotic are similar, except that there isstronger support for continuing the oral antipsychotic at the same dose until therapeutic drug levels of the injectableantipsychotic are achieved and then gradually tapering the oral antipsychotic compared with the other options.
It should be noted that the experts definitely do not recommend stopping the oral antipsychotic when the first long-actinginjection is given, since this would leave the patient without adequate antipsychotic coverage during the switchover andpotentially increase the risk of relapse.
When switching to:
First Line
High Second Line
Other Second Line
until patient achieves therapeutic bloodlevels of the injectable antipsychotic and gradually after giving the firstlong-acting injection Taper the oral antipsychotic gradually after levels of the injectable antipsychotic andthen immediately discontinue the oral 7F. Strategies When There Is a Partial ResponseQuestion 19We asked the experts about the appropriateness of a number of strategies to try to improve response in a patient who ishaving a partial but still inadequate response (e.g., a patient with some persisting positive symptoms). The experts gaveonly limited support to any of the options and rated many of them third line, probably reflecting the lack of empiricaldata concerning these strategies.
If partial response to:
First Line
High Second Line
Other Second Line
Add a long-acting injectable atypical antipsychotic Add a long-acting injectable atypical antipsychotic 7G. When to Switch to ClozapineQuestion 18Clozapine is indicated for treatment-refractory schizophrenia. However, clinicians vary in how they define treatment-refractory illness and there are no universally accepted criteria for treatment-refractoriness in schizophrenia. We there-fore asked the experts in what clinical situations they would be most likely to consider a switch to clozapine. The expertsconsider a trial of clozapine a strategy of choice for a patient who has failed to respond to adequate trials of one or moreconventional antipsychotics and two atypical antipsychotics. They would also consider it a strategy of choice for apatient who had failed to respond to trials of one or more conventionals and all the atypicals. However, 13% of theexperts rated this option third line, probably because there would be no advantage in trying all the other five atypicalantipsychotics before going to clozapine. The experts also consider a trial of clozapine a first line option for patients whohave failed to respond to trials of two or three atypicals or trials of one or more conventionals and one atypical. Althoughsome experts would consider clozapine for patients who have not responded to two conventionals or one atypical, therewas much less support for these options. When it is most appropriate to switch to clozapine remains an area of contro-versy with few data to inform clinical practice. We may in fact be doing our patients a disservice by trying multipledrugs before going to clozapine.
(bold italics = indications receiving the highest rating from at least 50% of the experts)
First Line
High Second Line
Other Second Line
Trials of one or more conventional antipsychotics
Trials of two conventional antipsychotics and two atypical antipsychotics
Trials of one or more conventional antipsychotics
and all of the other atypical antipsychotics
Trials of one or more conventional antipsychotics Optimizing Pharmacologic Treatment of Psychotic Disorders Guideline 8: Pharmacologic Strategies for Managing Relapse 8A. Relapse When Taking an Oral AntipsychoticQuestions 20–22If a patient relapses whom the clinician believes is compliant with medication based on all available evidence (e.g.,family report, plasma levels), the experts recommend (high second line ratings) either switching to a different oralantipsychotic or increasing the dose of the current medication. Another second line option the experts would consider isswitching to a long-acting injectable antipsychotic. This probably reflects concerns that the patient may not actually becompliant, since studies have found that clinicians are often incorrect in their assessment of patients’ compliance. It mayalso reflect concerns about absorption problems with the oral formulations.
When the clinician is unsure of the level of compliance or there is clear evidence of noncompliance, the experts’ firstline recommendation is to switch to a long-acting injectable atypical. They would also consider a long-acting conven-tional depot antipsychotic (high second line). If the clinician is unsure of the level of compliance, the experts would alsoconsider adding a long-acting atypical to the oral antipsychotic.
First Line
High Second Line
Other Second Line
*At the time of this survey, a long-acting injectable atypical antipsychotic was not available in the United States, although it wasavailable in several other countries. In the survey we asked the experts to rate how they would use such a formulation if it wereavailable.
8B. Relapse on a Long-Acting Injectable AntipsychoticQuestions 23, 54If a patient relapses when receiving a long-acting conventional antipsychotic (depot), the experts’ first line recommen-dation is to switch to a long-acting injectable atypical antipsychotic. They would also consider increasing the dose or thefrequency of injections of the long-acting conventional (high second line options).
If a patient relapses when receiving a long-acting injectable atypical antipsychotic, the experts’ first line recommenda-tion is to increase the dose of the injectable antipsychotic. They would also strongly consider adding the oral form of theinjectable antipsychotic to try to boost response (very high second line). The experts do not recommend switching to aconventional depot antipsychotic (third line rating).
Current Treatment
First Line
High Second Line
Other Second Line
*At the time of this survey, a long-acting injectable atypical antipsychotic was not available in the United States, although it wasavailable in several other countries. In the survey we asked the experts to rate how they would use such a formulation if it wereavailable.
Optimizing Pharmacologic Treatment of Psychotic Disorders Guideline 9: Dose Adjustment in Stable PatientsQuestion 24If the patient is being treated with an atypical antipsychotics or with fluphenazine or haloperidol decanoate, the majorityof the experts would continue maintenance treatment with the same dose that was effective acutely, although over 40%would lower the dose of olanzapine or risperidone. A majority of the experts said they would lower the dose of an oralconventional antipsychotic for maintenance treatment; however, the percentages are very close, with 40% or more of theexperts recommending continuing the acute dose of the conventional antipsychotic. The uncertainties shown in this areaare consistent with a lack of information concerning optimum doses for maintenance treatment with both conventionaland atypical antipsychotics.
Medications to continue at acute dose during
Target maintenance
maintenance treatment
dose if it is decided to
% of experts
Medications
lower dose*
endorsing this strategy
Atypicals
Conventionals
*The experts recommend waiting at least 6 months and prefera-bly a year after a patient has become stable before lowering thedose of the antipsychotic.Question 25 †The majority of the experts would not lower the dose of thismedication during maintenance treatment.
Guideline 10: Managing Complicating Problems 10A. Selecting Antipsychotics for Patients With Complicating ProblemsQuestion 26The experts consider clozapine the treatment of choice for patients who present with suicidal behavior. This is consistentwith a new indication for clozapine for “reducing the risk of recurrent suicidal behavior.” Clozapine is also the topchoice for aggression and violence. Other highly rated options for aggression and violence are risperidone (rated firstline), olanzapine, and a long-acting injectable atypical (both rated high second line). There were no first line recommen-dations for the other problems we asked about—dysphoria/depression, cognitive problems, and substance abuse—forwhich all of the oral atypical antipsychotics as well as a long-acting injectable atypical received second line ratings. Theexperts would also consider a long-acting depot conventional for a patient with substance abuse. The lack of first lineconsensus on these items probably reflects the fact that, although an increasing number of studies have looked at theeffects of atypical antipsychotics on mood, cognition, and substance use, the data are not yet sufficiently consistent ordramatic to influence clinical practice. It is interesting that the experts would not recommend oral conventional antipsy-chotics for patients with any of the problems that we asked about, except aggression/violence, for which conventionalorals were second line options. It is possible that these complicating problems may be caused or exacerbated by non-compliance. Therefore, it is not surprising that a long-acting atypical antipsychotic was a prominent alternative, espe-cially for aggression/violence and substance-abuse problems.
(bold italics = treatments of choice)
Complicating problem
First Line*
High Second Line
Other Second Line
Clozapine
*In this survey, we asked only about oral and long-acting injectable formulations of antipsychotics. Unless otherwise specified, allmedications listed in the tables refer to the oral formulation.
Optimizing Pharmacologic Treatment of Psychotic Disorders 10B. Selecting Adjunctive Treatments for Patients With Complicating ProblemsQuestions 27–30When we asked about a number of adjunctive medications that are commonly used in clinical practice to treat a varietyof complicating problems in patients with schizophrenia, the experts as a group had few strong recommendations, proba-bly reflecting the lack of decisive empirical data in this area. The only first line recommendation was a selective seroto-nin reuptake inhibitor (SSRI) for dysphoria/depression, reflecting studies showing that antidepressants can be helpful forpatients with comorbid depression. Venlafaxine was a very high second line for dysphoria/depression. For aggressionand violence, valproate and lithium received high second line ratings. For suicidal behavior, the same two antidepres-sants recommended for dysphoria/depression received high second line ratings, with ECT another high second lineoption. The question of how to treat persisting negative symptoms has long been a difficult issue in the field. Althoughthere was no consensus on any of the adjunctive treatments which were rated second line for negative symptoms, itshould be noted that approximately a quarter of the experts or more rated the following options first line: a glutaminergicagent, an SSRI, another antipsychotic, or venlafaxine.
Complicating problem
First Line
High Second Line
Other Second Line
Strategies for a Patient With Clinically Significant ObesityQuestions 31, 32 There is increasing concern about long-term medical problems in patients with schizophrenia, especially obesity and itscomplications. Many antipsychotics can contribute to weight gain and clinicians face difficult clinical dilemmas when apatient with clinically significant obesity (BMI ≥ 30) responds well to a medication that is likely to be contributing to thepatient’s weight problem. If a patient with clinically significant obesity has responded to an antipsychotic other thanclozapine, the experts recommend a trial of a different antipsychotic with less weight gain liability combined with nutri-tional and exercise counseling if possible. They would also consider (high second line) continuing the same antipsy-chotic and providing nutritional and exercise counseling to try to help the patient lose weight. However, reflecting thefact that most patients receiving clozapine have already failed to respond to other agents, the experts would continueclozapine in this situation and try to address the weight problem with nutritional and exercise counseling. Although theexperts gave a high second line rating to lowering the dose of clozapine in this situation, clinical studies have found thatweight gain does not appear to be a dose-related effect. It is interesting that the experts gave second line ratings to theaddition of topiramate. Although there have been case reports of weight loss with this agent in schizophrenia, there areno controlled studies supporting this practice. The experts did not recommend the use of weight loss medications(orlistat, sibutramine) or surgical treatment of obesity in this population.
Clinical presentation
First Line
High Second Line
Other Second Line
antipsychotic and providenutritional and exercise provide nutritional andexercise counseling antipsychotic with less weightgain liability and provide Optimizing Pharmacologic Treatment of Psychotic Disorders 10D. Monitoring for Comorbid Conditions and Risk FactorsQuestion 33
Many patients with schizophrenia rely on their psychiatric care provider for general medical care. With the improving
outcomes being achieved with the newer atypical antipsychotics, more attention is being focused on short- and long-term
health and wellness in this population. We asked the experts which conditions and risk factors they felt it was most
important to monitor. We also asked which ones it was feasible to monitor in a psychiatric treatment setting. The experts
felt that it was important to monitor for all the conditions we asked about, with obesity and diabetes considered the most
important (rated 9 by 60% and 56% of the experts, respectively). The experts’ ratings of feasibility reflect the relative
difficulty of the assessments involved (e.g., it is relatively simple to monitor weight and blood pressure, but much harder
to evaluate osteoporosis). Although we did not ask about obtaining lipid profiles, the editors note that clinicians should
also obtain lipid levels on a regular basis, because some antipsychotics are associated with hyperlipidemia. A recent
expert conference concluded that, as part of routine care, a lipid panel should be obtained if one is not available. Given
that individuals with schizophrenia, as a group, are considered to be at high risk for coronary heart disease, lipid screen-
ing should be carried out at least once every 5 years and more often when there is evidence of lipid levels that approach
those that would lead to treatment.* The same conference also recommended that clinicians should be aware of, and
monitor regularly for, symptoms of increased prolactin. If clinically indicated, prolactin should be measured, and, if
elevated, a work-up for the cause of the elevation should be initiated. Consideration should also be given to switching to
a prolactin-sparing medication—if the symptoms disappear and prolactin levels fall to normal, an endocrine work-up can
then be avoided. Recommendations on other complicating conditions, such as cardiac problems (QTc prolongation and
myocarditis), cataracts, and EPS will also be included in the Mount Sinai guideline when it is published.
(bold italics = conditions receiving the highest rating from at least 50% of the experts)
Conditions and risk
First Line
Second Line
factors to monitor for
Obesity
Diabetes
Obesity
Hypertension
*Marder SR, Essock SM, Miller AL, et al. The Mount Sinai Conference on the Health Monitoring of Patients with Schizophrenia. AmJ Psychiatry (submitted) Guideline 11: Levels of Compliance 11A. Defining Levels of ComplianceQuestion 36We provided the experts with the definitions of compliance given below to use as benchmarks in answering a series ofquestions about the assessment and management of compliance problems. We also asked them to tell us how they woulddefine levels of compliance. On average, the expert panel would set a higher threshold for compliance, as shown below,and would consider a patient who missed more than 65% of his or her medication noncompliant.
Level of compliance
Definitions provided in the survey
Average of experts’ preferred definitions
11B. Reported Extent of ComplianceQuestions 34 & 35Not surprisingly, the experts report that their patients show higher levels of compliance than are generally reported in theliterature.
Level of compliance
Levels reported in
Experts’ estimate of compliance
the literature
levels in their patients
Compliant (misses < 20% of medication) Partially compliant (misses 20%–80% of medication) Noncompliant (misses > 80% of medication) Guideline 12: Assessing ComplianceQuestion 37The experts consider asking the caregiver or patient first line strategies for assessing compliance; they would also con-sider pill counts, obtaining blood levels, and using self-rating scales. They did not consider routine use of urine testsappropriate.
Preferred strategies
Also consider
Optimizing Pharmacologic Treatment of Psychotic Disorders Guideline 13: When to Intervene for Compliance ProblemsQuestion 38The experts were unanimous about the need to intervene if a patient is missing more than 80% of medication. Theywould usually intervene if a patient is missing approximately 50% of prescribed medication (91% would usually inter-vene). The majority of the experts (52%) would also usually intervene when a patient is missing approximately 20% ofmedication. There was less agreement about whether to intervene if a patient is only missing occasional doses (13%would usually intervene, 39% would sometimes intervene, and 48% would generally not intervene).
(bold italics = over 50% of the experts gave the highest rating to intervention)
Usually intervene
Sometimes intervene
Patient missing more than 80%
of medication doses or has
stopped medication completely
Guideline 14: Strategies for Addressing Compliance Problems Selecting Initial StrategiesQuestions 39 & 40 We asked the experts about the appropriateness of three different types of strategies that have been used to addresscompliance problems: • Pharmacologic interventions (e.g., switching to a long-acting medication) • Psychosocial interventions (e.g., patient education, compliance therapy [focused cognitive-behavioral therapy tar- • Programmatic interventions (e.g., intensive case management, assertive community treatment) The experts gave first line ratings to all three types of interventions. The editors note that clinicians should generallyemploy a combination of strategies tailored to the specific needs of the patient. The experts gave the highest ratings topsychosocial interventions for patients who are partially compliant, probably reflecting findings that such interventionscan improve compliance levels. Psychopharmacologic interventions received the highest ratings for noncompliant pa-tients, probably reflecting the fact that patients who are not taking their medication are at the highest risk for relapse andit is especially important to try to get the patient back on medication as quickly as possible.
(bold italics = intervention of choice)
Clinical presentation
Preferred interventions to improve compliance
Psychosocial interventions
Pharmacologic interventions
14B. Psychosocial and Programmatic Interventions to Improve ComplianceQuestions 41 & 42Among psychosocial interventions for improving compliance, the experts gave the highest ratings to patient/familyeducation, medication monitoring, and compliance therapy. Their ratings agree with research findings concerning theefficacy of these strategies in improving compliance. Findings concerning the efficacy of group and individual psycho-therapy in improving compliance are equivocal, as shown by the lower ratings given to these options.
Among programmatic interventions the experts recommend assertive community treatment (ACT), ensuring continuityof treatment provider across treatment settings, and intensive case management services. These recommendations reflectfindings in the literature that intensive case management, in particular the kind of assistance provided by ACT programs,can significantly improve compliance levels. Lack of continuity in care providers can lead to serious compliance prob-lems, since patients may be continued on an ineffective or difficult-to-tolerate treatment regimen or may not receivecontinuing medication coverage after discharge. The experts also considered supervised residential services, partialhospitalization, rehabilitation services, and involuntary outpatient commitment useful options for improving compliance.
Psychosocial interventions
Programmatic interventions
Preferred
Also consider
Preferred
Also consider
contact 1–5 timesweekly or morefrequently as needed) Optimizing Pharmacologic Treatment of Psychotic Disorders Pharmacologic Strategies for Addressing Compliance ProblemsQuestions 43 & 44 There was strong agreement among the experts that the first line pharmacologic strategy for addressing complianceproblems is to switch the patient to a long-acting injectable atypical antipsychotic once this option is available (rated firstline for partially compliant patients and treatment of choice for noncompliant patients). High second line options are toswitch to a long-acting depot conventional or add a long-acting injectable atypical. Another high second line option for apatient who is partially compliant is to continue the same pharmacotherapy and intensify psychosocial interventions toimprove compliance. However, the experts do not recommend this strategy for a patient who is noncompliant.
(bold italics = treatment of choice)
Clinical presentation
First Line
High Second Line
Other Second Line
antipsychotic that has notpreviously been used pharmacotherapy; intensifypsychosocial treatment Switch to a long-acting
atypical antipsychotic
antipsychotic that has notpreviously been used *At the time of this survey, a long-acting injectable atypical antipsychotic was not available in the United States, although it wasavailable in several other countries. In the survey we asked the experts to rate how they would use such a formulation if it wereavailable.
III. LONG-ACTING INJECTABLE ANTIPSYCHOTICS Guideline 15: Benefits of Long-Acting Injectable AntipsychoticsQuestion 45The experts consider the greatest benefit of a long-acting injectable antipsychotic to be assured medication delivery.
Other important advantages are the ability to know immediately when a patient misses medication and the fact that thepatient continues to have some medication in his or her system even after a missed dose. Additional advantages are thereduced risk of relapse associated with continuous medication, and the ability to know that relapse, if it occurs, is not theresult of compliance problems.
(bold italics = benefits receiving the highest rating from at least 50% of the experts)
Most important
Somewhat important
Assured medication delivery
Knowing immediately when medication is missed Some continuing medication coverage after a missed dose Knowing that relapse has occurred despite adequate pharmacotherapy Guideline 16: Potential Disadvantages of Long-Acting Injectable The experts consider lack of patient acceptance the most important potential disadvantage of long-acting injectableantipsychotics. To some extent, this response probably reflects an assumption that patients will not accept the idea ofcontinuing injections. However, once they try a long-acting medication, many patients are surprised to find how easy itis to tolerate receiving medication in this way. Although lack of patient autonomy is another potential concern that issometimes mentioned, patient surveys do not support this as being a major factor. Although the experts said that theyconsidered inability to stop medication immediately should side effects become a problem somewhat important as apotential disadvantage, the editors were hard pressed to find examples of situations in which immediate discontinuationof an antipsychotic in a long-acting formulation was a medical necessity. Even in neuroleptic malignant syndrome, thereis no evidence that mortality rates are higher among patients receiving a long-acting injectable antipsychotic than inthose receiving an oral medication (assuming that the condition is identified and appropriately treated).
Most important
Somewhat important
Not too important
Inability to stop medication immediately should Stigma associated with injections or depot Optimizing Pharmacologic Treatment of Psychotic Disorders Guideline 17: Factors Favoring Use of Long-Acting Injectable In deciding whether to use a long-acting injectable antipsychotic, 96% of the experts consider the availability of anatypical antipsychotic in such a formulation very important. This probably reflects concerns about side effects associatedwith the conventional depot antipsychotics. Other factors that the experts consider very important in deciding to use along-acting injectable are good patient acceptance of the injection, evidence that the rate of relapses and side effects willbe lower than with oral equivalents, better quality of life for their patients, and ease of administration.
(bold italics = factors receiving the highest rating from at least 50% of the experts)
Most important
Somewhat important
Availability of an atypical antipsychotic in a long-
acting injectable formulation
Demonstrated superior efficacy to oral equivalent Demonstrated fewer relapses/hospital admissions than Little dose titration required with long-acting injectable Easy dose conversion from oral equivalent Better quality of life/patients say they feel better Easy dose conversion from other oral antipsychotic Guideline 18: Indications for Switching From an Oral Antipsychotic to a Long- Acting Injectable AtypicalQuestions 48 & 49 We asked the experts about the appropriateness of using a long-acting injectable atypical antipsychotic in a variety ofclinical situations. The experts consider a long-acting atypical antipsychotic the treatment of choice for a patient who istaking an oral atypical and requests the long-acting formulation, for a patient who relapses because of noncompliancewith an oral atypical antipsychotic, and for a patient who is experiencing EPS on a depot conventional antipsychotic. Theexperts consider a long-acting injectable atypical first line for a patient in involuntary outpatient commitment, for apatient who is chronically relapsing on an oral conventional, for a patient with lack of insight or denial of illness, for apatient taking an oral atypical antipsychotic who is relapsing for reasons that are unclear, and for a patient with a historyof aggressive or violent behavior. It is interesting that the experts perceive a role for the use of long-acting injectableatypicals that goes well beyond treatment of patients with compliance problems (see the many other second line indica-tions listed below). Of all the situations that we asked about, the only ones in which the experts would not generallyconsider a long-acting injectable atypical are a patient taking an oral atypical or conventional who is stable and notexperiencing EPS or a patient who has been newly diagnosed with schizophrenia and has had no previous antipsychotictreatment.
Further recommendations: We asked the experts how concern about the potential for TD would affect their decision to
switch to an injectable atypical antipsychotic. The majority of the experts would definitely switch if there is concern
about TD in a patient who is experiencing EPS on a depot or oral conventional antipsychotic (96% and 73% first line,
respectively). Even if the patient is not experiencing EPS, many of the experts would consider switching from a depot or
oral conventional if there is concern about TD (49% and 38% first line, respectively). The editors were unsure on what
basis a clinician would decide that there was in fact no or minimal risk of TD. Question 50
We asked the experts about the appropriateness of beginning treatment with a long-acting injectable atypical while the patient is hospitalized, given shorter lengths of hospital stays. This strategy was rated high second line by the expertpanel, in order to ensure continuing medication coverage when the patient is discharged and to facilitate acceptance of aninjectable medication in outpatient treatment. The experts also noted that this strategy may be helpful because patientsare most vulnerable to relapse soon after discharge.Questions 52 & 53 (bold italics = indications receiving the highest rating from at least 50% of the experts)
First Line
High Second Line
Other Second Line
Patient taking an oral atypical
antipsychotic who requests a long-acting
antipsychotic
Patient taking an oral atypical
antipsychotic who is experiencing relapse
because he or she stopped taking
medication
Patient taking a depot conventional
antipsychotic who is stable but
conventional antipsychotic who ishaving troublesome side effects experiencing EPS
antipsychotic who is chronically relapsing Persistent lack of insight/denial of illness Patient taking an oral atypical antipsychotic who is experiencing relapse for reasonsthat are unclear History of or potential for aggressive or Optimizing Pharmacologic Treatment of Psychotic Disorders Guideline 19: Factors Motivating Patients to Return for Repeat InjectionsQuestion 51The experts consider the influence of family/caregivers and physician/treatment team to be most important in motivatingpatients to return for repeat injections.
Most important
Somewhat important
Urging/insistence of family or caregivers Not having to remember to take oral medication Guideline 20: Indicators of Remission and RecoveryQuestion 55With improving outcomes, research studies are now trying to evaluate the effectiveness of different antipsychotics notonly in producing remission of symptoms but in promoting long-term recovery in patients with schizophrenia. However,as yet there is no general consensus on how best to define these terms. We therefore asked the experts to rate the appro-priateness of a number of factors as indicators of remission and recovery. There was strong agreement that the level ofpositive symptoms is the single most important indicator of remission. High second line indicators are levels of cogni-tive/disorganized, negative, and depressive symptoms, reflecting studies that show that these associated symptomscontribute in a substantial way to the functional disability associated with schizophrenia. In defining recovery, however,the experts gave almost equal weight to all of the indicators that we asked about, indicating that recovery is a conceptinvolving improvement in multiple domains.
Rank ordering of symptomatic indicators: When the experts were asked to rank order four key indicators of remission
and recovery, their responses agreed very closely with those presented in the table below: 89% considered level of
positive symptoms the most important indicator of remission, followed by cognitive/disorganized symptoms, negative
symptoms, and depressive symptoms, all three of which were ranked similarly. However, there was less agreement on
the most important indicator of recovery, with 41% considering level of positive symptoms most important, 33% giving
the highest ranking to level of cognitive/disorganized symptoms, and 28% ranking level of negative symptoms as most
important.Question 56
Rank ordering of functional outcomes. When asked to rank order three functional outcomes as indicators of remission,
the experts were divided, with 45% considering independent living, 32% occupational/education functioning, and 20%
peer relationships the most important functional indicator of remission. This division among the panel may reflect the
fact that one is unlikely to see major changes in any of these areas in the shorter time frame that is usually used to meas-
ure remission (see Guideline 21). However, when asked about the same functional outcomes as indicators of recovery,
the majority (64%) felt that occupational/educational functioning was the most important functional outcome in recov-
ery, followed by peer relationships (considered most important by 20%) and independent living (considered most im-
portant by 18%). When asked about the most appropriate way of defining functional improvement in their patients, 86%
of the experts considered relative rather than absolute change in the patient the most appropriate indicator.Questions 57 & 58
(bold italics = indicators receiving the highest rating from at least 50% of the experts)
Remission
Recovery
First Line
High second line
Other second line
First line
Level of positive
symptoms
Optimizing Pharmacologic Treatment of Psychotic Disorders Guideline 21: Severity and Duration of Symptoms as Indicators of Remission We asked the experts what levels of symptom severity were most appropriate to use in defining remission and recovery.
Their ratings are presented in the bar charts below. The majority of the experts would consider a patient in remissionwho had mild levels of positive, cognitive/disorganized, negative, and depressive symptoms (62%, 69%, 62%, and 73%of the experts, respectively). However, a third of the experts felt that no positive symptoms should be present for apatient to be considered in remission.
The experts’ ratings shifted to the left when asked about indicators for recovery, with a majority (62%) saying that thereshould be no positive symptoms for a patient to be considered in recovery. In terms of negative symptoms, 62% of thepanel would consider a patient in recovery who had mild negative symptoms while 33% would look for no negativesymptoms. The panel was more evenly split as to whether a patient could have mild cognitive or depressive symptomsand still be considered in recovery.
Duration of symptoms. The expert panel said that the improvement in symptomatic indicators should be maintained for
at least 3 months for a patient to be considered in remission and for a year or more for a patient to be considered in
recovery. The experts believe that improvement in functional indicators (occupational/vocational functioning, independ-
ent living, peer relationships) needs to be maintained for somewhat longer, 15–17 months, for the patient to be consid-
ered in recovery.
Severity of symptoms as indicators of remission and recovery
Remission
Recovery

Source: http://www.senon-online.com/Documentation/telechargement/guidelines/autres/JCP%20Optimizing_Antipsychotics_Guidelines.pdf