PSYCHOSIS/AUDITORY HALLUCINATIONS
| PSYCHOPHARMACOLOGIC TREATMENT OF PSYCHOSIS —Jonathan M. Meyer, MD, Assistant Professor of
Psychiatry, University of California, San Diego, School of Medicine, and Staff Psychiatrist, Veterans Affairs San Diego
Healthcare System
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| Differential diagnosis of psychosis: primary major psychiatric disorders that may have psychosis as symptom include
schizophrenia (which can start at any age), bipolar disorder (manic phase with psychotic features), schizoaffective
disorders, psychotic depression, and delusional disorder; many people in this population have dementia, delirium,
or both, especially those >65 yr of age; many medical conditions, such as Huntington’s disease and Parkinson’s
disease, can cause psychosis
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| Assessment and diagnostic tests: focused psychiatric history and examination; general physical history and examination;
routine cognitive examination or rating scale; focused neurologic examination; routine laboratory and drug
levels—urinalysis; complete blood cell count; basic chemistry screen; blood levels if patient takes digoxin, anticonvulsant,
or tricyclic antidepressant; if indicated—thyrotropin, other thyroid function tests, erythrocyte sedimentation
rate, serum vitamin B12 , serum folate, urine culture, toxicology screen, chest x-ray, electrocardiography
(ECG), electroencephalography (EEG), computed tomography (CT), or magnetic resonance imaging (MRI)
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| Choosing antipsychotic medication: “psychosis is a symptom everybody deserves a diagnosis”; once diagnosis established,
treat based on literature and clinical experience; for some conditions, such as Alzheimer’s disease with
psychosis, no treatment approved by Food and Drug Administration (FDA); all antipsychotic medications approved
for treatment of schizophrenia; all newer antipsychotic medications approved for acute mania; all antipsychotics
work well for positive symptoms of schizophrenia, but not as well for negative symptoms; for dementia, weigh risks
and benefits of antipsychotic medications
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 | Typical antipsychotic medications: designed to be strong blockers of dopamine D2 receptor; all equally effective if
given in large enough doses, but not all equal in side-effect profiles; some have side effects of sedation and/or
weight gain; some have anticholinergic side effects; some cause orthostatic hypotension; all have extrapyramidal
side effects; now used only rarely because of side effects
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| Atypical antipsychotic medications: called atypical because they produce improvement in schizophrenia without motor
side effects; include clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole; newest product,
paliperidone (Invega) extended-release tablet, is metabolite of risperidone; olanzapine, risperidone, and
aripiprazole available in rapidly dissolving form; olanzapine, ziprasidone, and aripiprazole available in injectable
form; all approved for schizophrenia, none approved for dementia; all designed to have less affinity for dopamine
receptor than typical antipsychotic medications, and to be strong serotonin 2A antagonists; study showed rate of tardive
dyskinesia approximately 10-fold less for risperidone than for haloperidol (Haldol)
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| Dopamine hypothesis of schizophrenia: dopamine binds tightly to dopamine receptor and produces strong postsynaptic
signal; all antipsychotic medications block dopamine receptors with differing degrees of strength; if typical antipsychotic
medication blocks all dopamine receptors and no signal gets into cell, motor side effects occur;
aripiprazole (Abilify) binds to dopamine receptor as tightly as dopamine, but produces weak postsynaptic signal
(≈25% of signal produced by dopamine itself), meaning that even if all dopamine receptors blocked by aripiprazole,
weak stimulation still occurs, reducing or eliminating motor side effects; in study of Alzheimer’s dementia
comparing olanzapine, quetiapine, and risperidone, people on placebo dropped out at same rate as those on antipsychotic
medications, but reasons for dropout differed; those on placebo dropped out because it did not work (but side
effects were minimal), and those on antipsychotic medications dropped out due to side effects; however, in separate
studies of aripiprazole, “the first 2 trials were complete failures; they didn’t separate from placebo at all; and in the
third trial, most of the drug arms didn’t separate either,” meaning aripiprazole not efficacious and not first-choice
medication in patients with Alzheimer’s dementia
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| Ziprasidone: not much data because it was thought to cause cardiac arrhythmia, but in retrospective chart review of
62 patients, ziprasidone found to cause no adverse cardiac events; most patients had no changes in ECG; drug
stopped in 9 of 62 patients because of noncardiac side effects or lack of efficacy; has advantage of being available
in injectable form
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| Summary of dosing: as people age, recommended doses get lower
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Schizophrenia
(young patients)
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| Conclusions: dementia—evidence suggests that risperidone and olanzapine useful in reducing aggression, and risperidone
reduces psychosis, but both associated with serious cerebrovascular events, mortality, and extrapyramidal
symptoms; despite modest efficacy, risperidone and olanzapine should not be used routinely to treat patients with
dementia and aggression or psychosis except in cases of marked risk or severe distress; delirium—comparative
studies suggest that antipsychotic medications efficacious, when compared with baseline, and safe for treatment of
delirium; haloperidol remains most studied agent, but recommendation of any agent as first-line intervention limited
by quantity and quality of data available; better studies needed
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| TRANSCRANIAL MAGNETIC STIMULATION FOR TREATMENT-RESISTANT AUDITORY
HALLUCINATIONS— Ralph Hoffman, MD, Professor of Psychiatry, Yale University School of Medicine, New
Haven, CT
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| Clinical features of auditory hallucinations: occur in 60% to 80% of patients with schizophrenia, 10% to 15% of patients
with mood disorders; in most cases, experienced as oral speech with recognizable timbre and content (“as
if a familiar person is speaking”), but occasionally experienced as other sounds (eg, rattling chains, breaking
glass); 50% of auditory hallucinations seem to come from outside of patient’s head; triggered by specific sounds
(eg, running water, air-conditioning unit, hum of automobile tires) in 30% of cases; auditory hallucinations resistant
to or respond poorly to medications in ≈25% of cases; among treatment-responsive patients, auditory hallucinations
are last positive symptom to remit and first positive symptom to reappear; cause high distress and
functional disability; perceived as being highly intrusive (“like being in a constant state of mental rape”); associated
with suicide and violence
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| Patient perceptions: “it’s like they’ve walked into another reality, a parallel reality that has a vividness and a
salience to them that is hard to describe but is very profound”; experiences with auditory hallucinations often
compelling to patients and have force of intimate personal relationship; patients often carry on conversations
with voices; auditory hallucinations may contribute to some negative symptoms of schizophrenia
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| Treatment: only ≈25% of auditory hallucinations respond to antipsychotic medications; cognitive behavioral therapy
(CBT) “really hasn’t taken hold,” probably because auditory hallucinations are “so automatic and so ultimately
out of the control of the patient”
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| Transcranial magnetic stimulation (TMS): during auditory hallucinations, positron emission tomography (PET)
showed activation of temporoparietal lobe–language processing area of brain; in trial of speech perception, subjects
asked to shadow spoken speech that was phonetically degraded; subjects with auditory hallucinations much
less able to discern words accurately; this led to 82% accuracy in researchers’ ability to discern people with auditory
hallucinations, suggesting that speech-perception neurocircuitry plays critical role in genesis of auditory hallucinations
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| TMS: electromagnetic coil positioned on scalp produces strong magnetic field that passes unperturbed through
scalp and bone and penetrates superficial cortex without spread and allows selective activation of brain; trials
showed that stimulation of cortex at relatively high frequency 10 to 20 times per second induces sustained activation
of cortex, but stimulation once per second produces sustained deactivation
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| TMS vs electroconvulsive therapy (ECT): ECT—uses brief pulses of direct electrical stimulation of brain; requires
anesthesia and medical monitoring; induces convulsion; memory difficulties and other cognitive problems common
side effects; TMS—uses more extended trains of magnetic stimulation; does not require anesthesia; does not
produce convulsion (“in fact, we try to avoid convulsions”); cognitive impairments rare
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| Speaker’s trials: first trial—used figure-of-eight coil over area of brain activation seen on neuroimaging; devised ingenious
sham treatment; delivered 40 min of stimulation over 4 days; involved only 12 patients and was primarily
safety trial; results showed statistically robust effects but modest clinical significance; improvements lasted from 1
day to 3 wk; anticonvulsant medications had strong negative effect on efficacy; treatment had no effect on symptoms
other than auditory hallucinations; second trial—same coil, same positioning, same sham treatment; involved
132 min of stimulation over 9 days; patients continued taking antipsychotic medications; 50 well-matched patients;
at end of trial, >50% of patients in active group reported at least 50% improvement in auditory hallucinations, compared
to 18% in placebo group; many patients maintained improvement for 10 to 20 wk, and small group maintained
for >1 yr; of subsequent studies by other research groups, more have been positive than negative; negative
studies tended to use lower doses of TMS
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| Continuing challenges: significant subgroup of patients did not respond to TMS; by tradition, language processing involves
Wernicke’s area, which is involved with receptive language (speech perception), and Broca’s area, which is
involved in language production; however, these functions overlap, eg, Broca’s area also involved in speech perception,
although to lesser extent than Wernicke’s area; in addition, other areas of brain also involved in language,
verbal imagery, and speech perception; primary auditory cortex critically involved in translating sound into phonetic
information, which is then parsed as speech; supramarginal tract and prefrontal areas also involved; studies of
brain activation found much intersubject variability in areas of brain activated by language processing, so another
trial was designed to allow for neuroimaging before TMS to determine whether targeting specific brain areas could
improve results of TMS treatment; “results weren’t that overwhelming,” although at least 1 of 8 patients had “a
very robust improvement”; unfortunately, few people with auditory hallucinations hallucinate often enough to do
this type of mapping; trial repeated on 8 patients who had continuous hallucinations, “and these results were somewhat
more promising”; when results of all trials compiled, found that TMS administered to Wernicke’s area
seemed to produce greatest amount of improvement
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| Maintenance repetitive TMS (rTMS): generally well tolerated; downward drift in one subset of California Verbal
Learning Test (CVLT), although other neuropsychiatric indices improved; patients often reported cognitive improvement,
ie, “that their mind felt less cluttered and they could focus more and they could read more readily”;
speaker concludes that improvements seem to be more robust and more sustained (40%-50% of patients in this trial
show persistent improvement up to 6 mo)
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| Recurrence of auditory hallucinations: patients allowed to return for second trial of TMS; speaker now investigating
bilateral simultaneous synchronous TMS, and early results promising
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| Summary: rTMS to speech-perception regions appears to produce critical improvement in many but not all patients
with persistent auditory hallucinations; rTMS generally well tolerated, although there is small risk for decrease in
memory and very small chance of seizure; improvements endure for weeks to months in many cases and may be
clinically significant; effects on symptoms other than auditory hallucinations mixed; most suitable for patients
whose dominant symptom is auditory hallucinations; responders may be predictable
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Suggested Reading
Arzy S et al: Induction of an illusory shadow person. Nature. 443:287, 2006; Ballard C, Waite J: The effectiveness of
atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst
Rev Jan 25:CD003476, 2006; Boutros NN et al: Electroencephalogram and repetitive transcranial magnetic stimulation.
Depress Anxiety 12:166, 2000; Burris KD et al: Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist
at human dopamine D2 receptors. J Pharmacol Exp Ther 302:381, 2002; Carlsson A: The current status of the
dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1:179, 1988; Greco KE et al: A retrospective study
of the safety of intramuscular ziprasidone in agitated elderly patients. J Clin Psychiatry 66:928, 2005; Hoffman RE et
al: Probing the pathophysiology of auditory/verbal hallucinations by combining functional magnetic resonance imaging
and transcranial magnetic stimulation. Cereb Cortex 17:2733, 2007; Hoffman RE et al: Selective speech perception
alterations in schizophrenic patients reporting hallucinated “voices.” Am J Psychiatry 156:393, 1999; Hoffman RE et
al: Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a
fifty patient sample. Biol Psychiatry 58:97, 2005; Hoffman RE et al: Transcranial magnetic stimulation and auditory
hallucinations in schizophrenia. Lancet 355:1073, 2000; Hoffman RE et al: Transcranial magnetic stimulation of left
temporoparietal cortex and medication-resistant auditory hallucinations. Arch Gen Psychiatry 60:49, 2003; Hoffman
RE et al: Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated
“voices.” Biol Psychiatry 46:130, 1999; Hoffman RE: Language processing and hallucinated “voices”: insights from
transcranial magnetic stimulation. Cognit Neuropsychiatry 6:1, 2001; Horacek J et al: Effect of low-frequency rTMS
on electromagnetic tomography (LORETA) and regional brain metabolism (PET) in schizophrenia patients with auditory
hallucinations. Neuropsychobiology 55:132, 2007; Jeste DV et al: Conventional vs. newer antipsychotics in elderly
patients. Am J Geriatr Psychiatry 7:70, 1999; Kane JM et al: Tardive dyskinesia: prevalence, incidence, and risk factors.
J Clin Psychopharmacol 8(4 Suppl):52S, 1988; Lacasse H et al: Systematic review of antipsychotics for the treatment
of hospital-associated delirium in medically or surgically ill patients. Ann Pharmacother 40:1966, 2006;
Schneider LS et al: CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s
disease. N Engl J Med 355:1525, 2006; Woerner MG et al: Prospective study of tardive dyskinesia in the elderly:
rates and risk factors. Am J Psychiatry 155:1521, 1998.
Educational Objectives
| The goals of this program are to help practitioners select appropriate antipsychotic medication for patients with psychosis
and to provide preliminary information on the use of transcranial magnetic stimulation (TMS) as treatment for
treatment-resistant auditory hallucinations. After hearing and assimilating this program, the clinician will be better
able to:
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| 1. Diagnose psychosis and differentiate it from dementia and delirium.
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| 2. Discuss the dopamine hypothesis of schizophrenia.
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| 3. Determine circumstances in which typical antipsychotic medications are preferable to atypical medications.
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| 4. Describe the clinical features of auditory hallucinations.
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| 5. Discuss the early results of trials that used TMS to treat auditory hallucinations.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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. Meyer has received research grants
from Bristol-Myers Squibb and Pfizer; is a speaker and consultant for Bristol-Myers Squibb, Pfizer, and Janssen; and is a
consultant for Wyeth.
Acknowledgments
Dr. Meyer was recorded at the West Coast Geriatric Psychiatry Conference, held March 7-10, 2007, in San Diego, CA,
and sponsored by the University of California, San Diego, School of Medicine. Dr. Hoffman was recorded at the Second
Annual UC Davis Conference on Psychotic Disorders, held September 6, 2007, in Sacramento, CA, and sponsored
by the University of California, Davis, School of Medicine and the Sacramento County Division of Mental Health.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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