TREATMENT-RESISTANT SCHIZOPHRENIA
From Individuals With Serious Mental Illness: Optimizing Understanding, Treatment, and Recovery, presented by
Loma Linda University School of Medicine and Patton State Hospital
Donald C. Goff, MD, Director, Schizophrenia Program, Massachusetts General Hospital, Boston
Educational Objectives
| The goal of this program is to improve the management of treatment-resistant schizophrenia. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Differentiate between treatment resistance and treatment noncompliance in patients with schizophrenia.
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| 2. Identify factors that contribute to treatment noncompliance.
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| 3. Select appropriate doses of atypical antipsychotics for treating schizophrenia.
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| 4. Determine those cases in which combination therapy is appropriate for the treatment of schizophrenia.
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| 5. Manage some of the side effects of atypical antipsychotic medications.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Goff has received grants
or honoraria from Pfizer, Cephalon, Jannsen, Lilly, Bristol-Myers Squibb, Verus Med, Vanda Pharmaceuticals, Organon, Xytis,
Wyeth, and Forest Laboratories; he is a consultant to Xenoport and Dainippon Sumitomo Pharma America; is on the advisory
board of Solvay/Wyeth, Bristol-Myers Squibb, Vanda Pharmaceuticals, Organon, and Xytis; and is on the Data Safety
and Monitoring Board of Solvay/Wyeth. The planning committee reported nothing to disclose.
Acknowledgements
Dr. Goff was recorded at Individuals With Serious Mental Illness: Optimizing Understanding, Treatment, and Recovery,
held April 2, 2008, in Loma Linda, CA, and sponsored by Loma Linda University School of Medicine and Patton
State Hospital. The Audio-Digest Foundation thanks Dr. Goff and the sponsors for their cooperation in the production
of this program.
| Introduction: current treatment approach to schizophrenia focuses on quality of life rather than only on psychotic symptoms,
because “some patients do remarkably well despite persistent voices or delusions”; speaker posits that quality of
life affected more by negative symptoms and cognitive deficits than by psychotic symptoms
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| Selection of antipsychotic medication: select most effective drug that is medically benign (ie, causes fewest medical
complications) and that patient will take reliably
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| Diagnostic considerations: confirm diagnosis of schizophrenia; substance abuse most commonly missed comorbidity;
rule out psychotic depression, mania, drug toxicity, and delirium, or psychosis caused by medications for other conditions;
identify psychosocial stressors
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| Schizophrenia treatment algorithm: select antipsychotic that balances effectiveness with tolerability; if patient
does not do well, it is usually because he or she is noncompliant or does not tolerate side effects, or drug is not effective
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| Noncompliance: most clinicians aware of statistic that 70% of patients with schizophrenia do not take medications as prescribed,
but most believe their own patients 100% compliant; Medication Events Monitoring System (MEMS) uses pill
bottles with caps that record every time bottle opened; studies using this system show “it’s not as if there are compliant
patients and noncompliant patients”; rather, eg, some patients compliant half of time, some three-quarters of time, some
compliant for 3 wk then stop medication for 1 wk; patterns of noncompliance vary from patient to patient, but, in general,
medication not taken as prescribed; consequences of noncompliance include incomplete response, relapse, invalid dose titration,
and attribution of relapse to inadequate efficacy of medication rather than to inadequate compliance; alliance between
patient and physician often suffers
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| Factors that contribute to poor compliance: lack of insight—many patients do not have capacity to understand that they
are ill and do not appreciate that medicines have value; studies show insight not related to intelligence, but to amount
of distress or suffering; eg, patients tend to associate anxiety and depression with being ill, while delusions not perceived
as suffering; consequently, if medicine relieves anxiety or depression, patients likely to take it, but if medicine
for delusions, patients may not take; other factors—complicated regimen; substance abuse; side effects; poor symptom
control
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| To improve compliance: recognize that often, patients choose to take medication for own personal reasons, rather than
for reason intended by therapist; understand what patient wants in life (eg, job, marriage, social acceptance) and focus
treatment on his or her goals (not on therapist’s goals); avoid side effects; involve patient and family members in medication
decisions; try to improve patient’s sense of well-being by treating insomnia, depression, and anxiety
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| Depot medications: adherence certain; peak concentrations reduced, which may reduce side effects; use relieves caretakers
of burden of medication supervision
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| Dosing atypical antipsychotic medications
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| Risperidone: for most patients, optimal dose 4 to 6 mg/day; in studies, no evidence that either dose more effective; neurologic
side effects increase with doses >6 mg/day; available in depot form (Consta depot); in studies, 25-mg dose seemed
more effective for negative symptoms, whereas 50-mg dose more effective for psychotic symptoms; if patient not psychotic,
negative symptoms may be side effect of higher dose, and reducing dose may reduce negative symptoms
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| Olanzapine: curve for occupation of D2 receptors similar to that for risperidone; optimal dose seems to be ≈30 mg/day; in
study of patients still symptomatic after 8 wk, increasing dose to 40 mg/day produced continued improvement
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| Quetiapine: low affinity for D2 receptors; optimal dose “complete mystery”; early studies found no differences in doses
ranging from 150 to 750 mg/day; later study suggested ≈500 mg/day more effective than lower doses, but difficult to
determine clear dose-response rate; some studies have pushed doses to 1200 to 1500 mg/day, but none has shown evidence
of efficacy at these high doses; how to manage nonresponders unknown; speaker suggests pushing dose to 500
to 700 mg/day
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| Ziprasidone: during initial studies to determine D2 -receptor occupancy, miscalculation led manufacturer to estimate 20
mg bid as optimal dose; consequently, studies not done with doses >80 mg bid, but speaker suggests such doses may
benefit some patients; ziprasidone absorption from gut poor, unless taken with food (in which case, absorption levels
50% higher); therefore, before increasing dose, be sure patient taking ziprasidone with food; studies of higher doses
under way
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| Aripiprazole: binds tightly to D2 receptors; no evidence for improved outcomes with doses >10 mg/day; speaker speculates
that doses typically used probably “twice as high as we really need to achieve full occupancy”; half-life of aripiprazole
so long that 1 wk after last dose, D2 occupancy still close to 100%; if dose increased, takes 1 to 2 wk to get
new blood levels, and “we’re probably attributing the better response to higher doses, when it’s probably just the time
that has elapsed”; fortunately, higher doses do not cause worse side effects
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| Summary of efficacy of higher doses: only good evidence to support pushing doses of olanzapine; evidence for pushing
doses of quetiapine and aripiprazole poor; ziprasidone studies under way
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| Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): multicenter comparative trial of antipsychotic
drugs in ≈1600 patients; found antipsychotics fell into 3 categories, with clozapine appearing most effective,
olanzapine having intermediate efficacy, and all other antipsychotics about equal; higher-dose clozapine and olanzapine
most likely to produce response if other drugs fail, but also cause most metabolic side effects; if patient needs clozapine
or olanzapine, warn him or her and family of risks and monitor closely
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| Clozapine: some evidence that obtaining clozapine blood levels might be useful; only one study has prospectively and
randomly assigned patients to different blood levels (low, medium, and high); medium range just as effective as high
range and had fewer side effects; unable to predict blood levels from doses given, due to great variability in how clozapine
metabolized by different people; cigarette smoking dramatically lowers clozapine blood levels (by ≤50%)
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| Combination therapy: controversial; in California and other states, must justify combining antipsychotics; possible indications
include treatment resistance, supplemental symptom control (eg, insomnia), and treatment intolerance (may
reduce side effects of both drugs); first combination studied was sulpiride (not available in United States) added to
clozapine, and improvement seen in negative and psychotic symptoms; another study in which 4 mg/day of risperidone
added to clozapine also showed improvement in negative and psychotic symptoms (several negative studies used only
2-3 mg/day of risperidone); monitor additive side effects (addition of second antipsychotic may produce elevation in
prolactin levels); if patient responds to combination, document thoroughly; if patient does not respond, discontinue
combination
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| Real problem: occurs when inpatient physicians start adding drugs “because they feel obligated to do something and
outpatient doctors are always very reluctant to stop medicines that the inpatient doctors have used”; most patients get
better just by being hospitalized, so difficult to determine if improvement due to additional drugs
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| Cross-titration: when patient being switched from one medication to another, first medicine is slowly tapered down while
second is slowly tapered up; however, sometimes process gets interrupted and patient remains on both drugs “forever”;
see patient while he or she is on both drugs (not uncommon for patients to say they felt better when on both drugs; if
patient to remain on both drugs, document thoroughly that combination better than monotherapy)
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| Combinations to eschew: fluvoxamine can increase blood levels of some drugs (especially clozapine); anticonvulsants
(eg, carbamazepine [eg, Tegretol], phenytoin [Dilantin]) can dramatically lower blood levels of antipsychotics, so use
judiciously; adding thioridazine (Mellaril) to ziprasidone can cause dangerous prolongation of QT interval; adding anticholinergic
medication to clozapine can result in constipation, fecal impaction, and other gastrointestinal problems
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| Other combinations: selective serotonin reuptake inhibitors (SSRIs)—good evidence of usefulness for negative symptoms
and depression; new evidence suggests SSRIs may be best treatment in schizophrenia prodrome and may even
prevent progression from prodrome to full-fledged schizophrenia; lithium—some patients seem to do better with supplemental
lithium, even though they do not have affective syndrome; usually effective only in schizoaffective disorders,
but “often worth trying in patients who are failing all else”; lamotrigine—good evidence for adding it to
clozapine; methylphenidate (eg, Ritalin)—speaker has used successfully in college students who complain of not being
able to concentrate or to get out of bed before noon when taking clozapine; methylphenidate 5 mg bid seems to improve
attention, wakefulness, concentration, and function; some patients have continued combination into working
life; also consider using modafinil (Provigil)
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| Conclusions: if patient not responding to antipsychotic, confirm diagnosis; verify patient not using alcohol or drugs;
make sure patient actually takes drugs (consider depot formulation if compliance questionable); if patient still symptomatic,
consider olanzapine (pushing dose), then clozapine, but be aware of side-effect profiles and monitor carefully; little
evidence for combination therapies, but consider adding risperidone or using combinations discussed above if patient on
optimal dose of clozapine
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| Q and A 1: polypharmacy (especially when >1 antipsychotic included) works for some patients; however, too often drugs
added for wrong reasons and in an unsystematic way; important to optimize monotherapy before adding second drug
and document results carefully; because schizophrenia “such a disabling, dangerous, horrible illness,” patients deserve
continuing attempts at treatment
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| Q and A 2: paliperidone metabolite of risperidone; Invega brand name for slow-release paliperidone; when risperidone
used, blood contains approximately two-thirds paliperidone and one-third risperidone; when paliperidone used, blood
contains all paliperidone; “it’s hard to understand why paliperidone would be more effective than risperidone,” although
paliperidone may be somewhat better tolerated
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| Q and A 3: difficult to reconcile results of trial participants with real-life patients; CATIE was attempt by National Institutes
of Mental Health (NIMH) to develop treatment for real-life patients, who tend to be more complicated than research
subjects, less compliant, and have multiple diagnoses; efforts ongoing to study patients more representative of
real practices
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| Q and A 4 and 5: elevated prolactin levels in and of themselves of no concern, but “there is a little bit of a concern about
higher rates of breast cancer, which has never been resolved”; elevated prolactin of concern when estrogen lowered so
much that woman stops menstruating; speaker suggests if woman taking risperidone (which can elevate prolactin levels),
ask her whether her menstrual periods have stopped and, if so, switch from risperidone to prolactin-sparing antipsychotic
or consult with her primary care physician or gynecologist to correct prolactin levels
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| Q and A 6: blood testing essential for patients on clozapine; if patient needs to be on clozapine but refuses blood tests, try
to destigmatize need for clozapine and for blood tests; at speaker’s institution, patients on clozapine invited to socialize
at blood-drawing clinics
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| Q and A 7: sulpiride is D2 antagonist; not available in United States
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| Q and A 8: adding olanzapine to risperidone common, but “why it should work, we have no idea”
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| Q and A 9: aripiprazole tightly binds to D2 receptor, so adding it to another drug displaces other drug from D2 receptors, decreasing
efficacy; if patient on olanzapine gaining weight, switching to aripiprazole usually results in relapse; however, aripiprazole
added to small dose (eg, 5 mg) of olanzapine seems to be effective and keeps patient stable; reason unknown
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| Q and A 10: if patient on clozapine merely drooling, place towel on pillow (“most people can tolerate it”); clozapine impairs
swallowing of saliva, but does not increase production of saliva; therefore, aspiration possible; if patient complains
of drooling, ask if he or she awakens at night choking on saliva; if so, “that’s very dangerous”; decrease dose of
clozapine until choking stops; do not add anticholinergic drug to decrease saliva because clozapine already “extremely”
anticholinergic, and adding another anticholinergic drug can cause constipation, toxic bowel, bowel perforation,
and other gastrointestinal complications; some mouth sprays available that dry secretions
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| Q and A 11: nicotine patches do not lower clozapine blood levels; however, non-nicotine components of cigarette smoke
do lower clozapine blood levels; nicotine effective at improving cognition in patients with schizophrenia, so if patients
self-medicate with cigarettes to improve cognition, switching to nicotine patches may help eliminate smoking
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Suggested Reading
Arbuckle MR et al: Psychiatric opinion and antipsychotic selection in the management of schizophrenia. Psychiatr
Serv 59:561, 2008; Carpenter WT, Buchanan RW: Lessons to take home from CATIE. Psychiatr Serv 59:523,
2008; Chakos M et al: Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia:
a review and meta-analysis of randomized trials. Am J Psychiatry 158:518, 2001; Freudenreich O et al: The
evaluation and management of patients with first-episode schizophrenia: a selective clinical review of diagnosis, treatment,
and prognosis. Harv Rev Psychiatry 15:189, 2007; Freudenreich O, Goff DC: Antipsychotic combination therapy in
schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 106:323, 2002; Goff DC et
al: Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol
27:582, 2007; Gupta M: Clozapine and co-prescribed psychotropics: a short report. Clin Pract Epidemol Ment Health
4:11, 2008; Henderson DC et al: Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality:
results of a 10-year naturalistic study. J Clin Psychiatry 66:1116, 2005; Jubelt LE et al: Effects of transdermal nicotine
on episodic memory in non-smokers with and without schizophrenia. Psychopharmacology (Berl) 199:89, 2008; Kinon
BJ et al: Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized,
double-blind, fixed-dose study. J Clin Psychopharmacol 28:392, 2008; Lieberman JA et al: Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic
schizophrenia. N Engl J Med 353:1209, 2005; McEvoy JP et al: CATIE Investigators. Effectiveness of clozapine versus
olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic
treatment. Am J Psychiatry 163:600, 2006; Meyer JM et al: Change in metabolic syndrome parameters
with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr Res 101:273,
2008; Pani L et al: Practical issues with amisulpride in the management of patients with schizophrenia. Clin Drug Investig
28:465, 2008; Stroup TS et al: The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull 29:15, 2003;
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(CATIE) schizophrenia trial. Schizophr Bull 29:33, 2003; Taylor DM et al: Prior antipsychotic prescribing in
patients currently receiving clozapine: a case note review. J Clin Psychiatry 64:30, 2003; Volavka J et al: Clozapine,
olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder.
Am J Psychiatry 159:255, 2002; Wehmeier PM et al: Myocarditis, pericarditis, and cardiomyopathy in patients
treated with clozapine. J Clin Pharm Ther 30:91, 2005; Weissman EM: Antipsychotic prescribing practices in the Veterans
Healthcare Administration -- New York metropolitan region. Schizophr Bull 28:31, 2002.
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