BIPOLAR DISORDER/GERIATRIC PSYCHIATRY
From Helpful Highlights from Heartsome Heedful Headliners, presented by the University of Wisconsin School of
Medicine and Public Health and the Madison Institute of Medicine, Inc.
| NEW DATA ON MEDICATION TREATMENTS FOR BIPOLAR DISORDER —Steven L. Dubovsky, MD, Professor
and Chair, Department of Psychiatry, State University of New York at Buffalo; Adjoint Professor of Psychiatry
and Medicine, University of Colorado Medical Center, Denver
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| Evidence-based review of studies of mood stabilizers: review of 81 double-blind placebo-controlled trials;
study concluded that 1) not enough data to evaluate efficacy of any drug in reducing frequency or severity of one
kind of episode, while not increasing frequency or severity of another kind, and 2) only lithium fulfills all 4 criteria
for mood stabilizers, whether equivalence trials included or not (ie, lithium provides prophylaxis against and treats
mania and bipolar depression)
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| Lithium: recent reliable finding that bipolar mood disorders associated with hyperactive intracellular calcium
signaling, and many people with bipolar mood disorder have excessive amount of free calcium ions inside cells
throughout body; lithium reduces hyperactive calcium signaling within cells; lithium neuroprotective but causes
cognitive impairment and interferes with insulin signaling; with half-life of 24 hr, lithium can be dosed once
daily or once every other day, resulting in fewer adverse effects; optimal serum levels controversial; speaker recommends
“aiming for the highest level that the patient can tolerate” (usually 0.8 to 1.0 mEq/L in adults; children
may need higher serum lithium levels to achieve optimal brain lithium levels); no difference between treatment
for acute episode or maintenance
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| Antipsychotic medications: all antipsychotic medications, typical and atypical, work for mania (also, all neuroleptic
drugs and all benzodiazepines, except alprazolam [Xanax; has antidepressant properties and makes mania
worse] work for mania)
|
 | Olanzapine (Zyprexa): studies show olanzapine and valproic acid (Depakote) equally effective in treating mania,
but olanzapine causes more weight gain; in study of adolescent mania, olanzapine found to be better than placebo,
but in just 3 wk, 20% of patients developed elevated cholesterol levels and half had clinically important
weight gain
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| Ziprasidone (Geodon): study found that among patients who remained in study, ziprasidone associated with
long-term improvement in bipolar illness; however, two-thirds of patients dropped out before end of first year
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| Combination of olanzapine and fluoxetine (Prozac): half of patients in treatment arm and two-thirds in placebo arm
dropped out; of those who remained, fluoxetine alone or in combination better than placebo; speaker concludes
that combination of fluoxetine 50 mg and olanzapine 20 mg per day works as well in patients with bipolar depression
who stayed in study as fluoxetine 20 mg per day works in patients with unipolar depression; also, no increased
mania seen during 8-wk study; however, absence of increased mania in this short period no indication
that olanzapine will prevent long-term destabilization of mood by fluoxetine
|
| Quetiapine (Seroquel): manufacturer designed study and helped write report that aided in obtaining Food and Drug
Administration (FDA) approval for drug’s use in bipolar depression; speaker questions this study as basis for
widespread use of quetiapine as first-line treatment for bipolar depression
|
| Clozapine (eg, Clozaril): no placebo-controlled studies in bipolar illness, “but there’s a lot of experience with it”;
many clinicians find clozapine helpful for refractory complex bipolar illness, but difficult to use
|
| Anticonvulsants: valproic acid—no studies show correlation between blood levels of valproic acid and clinical
response, but studies show rate of increase of valproic acid level may be as important as final level; levels of
≈100 µg/mL provide most consistent results (higher levels cause increase in side effects without proportional increase
in benefits)
|
| Lamotrigine (Lamictal): in 18-mo study, 36% of patients remained nondepressed on lamotrigine vs 27% on placebo
(“not a tremendous difference”); in another study on preventing recurrences of mania, lamotrigine no better
than placebo; speaker concludes that lamotrigine “is not a bad drug for depression; I think the evidence that it’s a
mania drug is pretty flimsy”
|
| Oxcarbazepine (Trileptal): only 4 small studies on use of oxcarbazepine in bipolar disorder; all showed oxcarbazepine
better than placebo and equal to other anticonvulsants in preventing mania
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| Zonisamide (Zonegran): no controlled studies; 2 open-label studies indicate usefulness, but high drop-out rates due
to side effects; study comparing zonisamide to placebo showed zonisamide effective in promoting weight loss
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| Levetiracetam (Keppra): new anticonvulsant that acts on calcium signal; in few open studies, seemed helpful for
mania and depression in bipolar illness, but data limited
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| Negative anticonvulsant studies: topiramate (Topamax) no better than placebo in several controlled mania trials;
gabapentin (eg, Neurontin) showed no efficacy in placebo-controlled add-on study, and no benefit in rapid cycling;
tiagabine (Gabitril Filmtabs) showed no benefit in open trials of 47 patients with refractory bipolar disorder,
and 4 nonepileptic patients had seizures
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| Endocrine modulators: abnormality of hypothalamic-pituitary-adrenal (HPA) axis occurs in all mood disorders,
and many trials aimed at correcting this abnormality
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| Mifepristone (RU-486): progesterone antagonist at low doses, cortisol glucocorticoid receptor antagonist at higher
doses; short-term adjunctive use rapidly reduces psychotic depression, but serum cortisol increases with long-
term use, so not practical as maintenance treatment; no long-term studies
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| Thyroid augmentation: one controlled study and several open trials in bipolar illness; large doses of thyroxine
added to mood stabilizers resulted in improvement of complex mood disorders, but also raised serum thyroxine
levels to hyperthyroid range; double-blind substitution of placebo in some patients caused relapse; risks include
hyperthyroidism, atrial fibrillation, and osteoporosis
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| Omega-3 fatty acids: initial 4-mo study seemed to show efficacy, but replication failed; data limited
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| Second-messenger therapy: treatment of bipolar disorder with lithium, carbamazepine (eg, Tegretol), or verapamil
causes calcium signal to return to normal; verapamil—advantages include no weight gain, blood tests unnecessary,
no cognitive impairment, inexpensive, and safe in pregnancy; disadvantages include 3 to 4 times per day
dosing (sustained-release form does not work well in bipolar illness); nimodipine—most useful for people with
frequent mixed episodes and rapid alternations of dysphoric hypomania and depression; use only as adjunct to
other agents
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| Tamoxifen: estrogen-receptor antagonist and protein kinase C inhibitor at similar doses; open trial suggested antimanic
effect, but number of patients small; small 3-wk double-blind study showed tamoxifen better than placebo;
not practical for long-term use unless patient has breast cancer
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| PSYCHIATRIC MANIFESTATIONS OF LATE-LIFE MEDICAL ILLNESS —Ronald W. Pies, MD, Professor of
Psychiatry, State University of New York Upstate Medical University, Syracuse, and Clinical Professor of Psychiatry,
Tufts University School of Medicine, Boston, MA
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| Comorbid medical conditions in depressed elderly: selected studies show 9% to 46% of elderly psychiatric
patients have comorbid medical conditions; 75% had ≥1 comorbid medical conditions requiring first-line treatment,
50% had 2, and 25% had ≥3; comorbid physical illness and cognitive impairment associated with functional
impairment at discharge
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| Physiologic changes in elderly: reduced lean body mass, increased fat (fat reservoir for fat-soluble drugs; except
for lithium, “virtually all of the psychotropic drugs are fat soluble”); reduced hepatic blood flow results in slowed
hepatic metabolism; decreased glomerular filtration; decreased creatinine clearance; increased brain monoamine
oxidase (MAO)-B, which decreases amines; increased neuronal sensitivity to sedative drugs
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| Medical causes associated with psychosis in elderly: thyroid, adrenal, and parathyroid hyper- or hypofunction;
hypoxia; renal and hepatic failure; electrolyte abnormality; meningoencephalitis; HIV infection; neurosyphilis;
central nervous system (CNS) tumors; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease;
Wilson’s disease; lupus; temporal arteritis; psychosis-inducing drugs include corticosteroids, amphetamines, cocaine,
levodopa, bromocriptine, disulfiram, anticholinergics, alcohol, bupropion, and antidepressants
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| Medical causes associated with Schneiderian first rank symptoms of psychosis: temporal lobe malignancy;
viral encephalitis; temporal lobe epilepsy; hydrocephalus; basal ganglia disease; hypothyroidism; Addison’s
disease; drugs; toxins
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| Sorting it out: organic psychotic conditions usually characterized by paranoid delusions, and persecutory thoughts
and ideas of reference; may resemble paranoid schizophrenia, but delusions in organic disease usually concrete,
non-bizarre, and changeable; chronic schizophrenia, on other hand, characterized by delusions that are abstract, bizarre,
and relatively unchanging
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| Medical causes of perceptual disturbances in elderly: alcoholic hallucinosis (“delirium tremens”; “DTs”);
complex partial seizures; migraine variants; posterior occipital lesions; narcolepsy; drugs and toxins, including anticholinergics,
amphetamines, barbiturates, cocaine, hallucinogens, and phencyclidine (PCP); pearl—dilated pupils
that respond briskly to light suggest stimulant overdose; if pupils respond sluggishly, consider anticholinergic
toxicity
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| Medical causes of depression in elderly: viral illness; malignancies; endocrine disorders; hematologic disorders;
cerebrovascular disorders; collagen vascular disease; degenerative CNS disease; drugs and toxins (some antihypertensive
drugs; β-blockers controversial); sleep disorders; pearls—patients with Huntington’s disease may
present with suicidality before chorea seen; poststroke depression more likely acute with left frontal and basal ganglia
lesions; later, any lesions can lead to depression, but more likely related to whether patient in nursing home,
hospital, or at home; in study, psychiatric consultation/liaison service found most common causes of depression in
medical patients were stroke, Parkinson’s disease, lupus cerebritis, HIV infection, hypothyroidism, and multiple
sclerosis
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| Organic causes of mania in elderly: extrapyramidal disease; subcortical dementia; CNS infections; CNS tumors;
demyelinating disease; temporal lobe epilepsy; systemic illness (eg, hyperthyroidism, uremia, pellagra);
drugs, including corticosteroids, levodopa, amphetamines, cocaine, cyclobenzaprine, yohimbine, and clarithromycin;
pearl—steroids can cause depression or mania
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| Medical causes of anxiety in elderly: cardiopulmonary disease; endocrine disease; gastrointestinal disease;
meningoencephalitis; metabolic disturbances; drugs and toxins
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| Organic causes of personality disturbance in elderly: trauma (especially to frontal lobes); demyelinating disease;
brain tumor; brain aneurysm; toxic encephalopathies; degenerative CNS disease; temporal lobe epilepsy
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| When to have high suspicion for undetected medical illness in elderly: complicated medical history; use of
many medications, including over-the-counter medications and herbal preparations; abnormal autonomic signs; recent
change in mental status; abnormal mental status (especially visual, olfactory, or tactile hallucinations, poor
memory, or fluctuating level of consciousness); signs of poor hygiene, neglect, or abuse
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| Pitfalls in diagnosis of medical causes: assuming that symptom (eg, catatonia) equals diagnosis; assuming psychodynamic
factors cause; taking incomplete medical and drug history; obtaining incomplete physical and laboratory
tests; performing inadequate mental status examination
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| Physical and laboratory studies that should be done in elderly with unexplained psychiatric symptoms: vital signs;
gross physical examination; complete blood cell count (CBC); electrolytes; serum urea nitrogen (BUN); creatinine
level; glucose level; VDRL test; liver function tests (LFTs); thyroid function tests; calcium level; urinalysis
and urine drug screen; maybe electroencephalography (helpful in confirming and monitoring delirium); ancillary
studies as indicated
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| Conclusions: “the body can have as many diseases as it pleases”; elderly patients with new-onset psychiatric symptoms
should be assumed medically ill until proven otherwise; do not use psychodynamic factors or precipitants as
means of ruling out organic disease
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Suggested Reading
Bauer MS, Mitchner L: What is a “mood stabilizer”? An evidence-based response. Am J Psychiatry 161:3, 2004;
Cummings JL: Clinical Neuropsychiatry. Orlando: Grune & Stratton, c1985; Dubovsky SL: Treatment of bipolar
depression. Psychiatr Clin North Am 28:349, 2005; Fujikawa T et al: Silent cerebral infarctions in patients with
late-onset mania. Stroke 26:946, 1995; Martin J et al: Assessment and treatment of sleep disturbances in older
adults. Clin Psychol Rev 20:783, 2000; Moore CM et al: Brain-to-serum lithium ratio and age: an in vivo magnetic
resonance spectroscopy study. Am J Psychiatry 159:1240, 2002; Post RM et al: Morbidity in 258 bipolar outpatients
followed for 1 year with daily prospective ratings on the NIMH life chart method. J Clin Psychiatry 64:680,
2003; Proctor EK et al: Comorbid medical conditions among depressed elderly patients discharged home after
acute psychiatric care. Am J Geriatr Psychiatry 11:329, 2003; Rundell JR, Wise MG: Causes of organic mood
disorder. J Neuropsychiatry Clin Neurosci 1:398, 1989; Sanger TM et al: Olanzapine in the acute treatment of bipolar
I disorder with a history of rapid cycling. J Affect Disord 73:155, 2003; Simon NM et al: STEP-BD Investigators.
Pharmacotherapy for bipolar disorder and comorbid conditions: baseline data from STEP-BD. J Clin
Psychopharmacol 24:512, 2004; Soreff SM, McNeil GM: Handbook of Psychiatric Differential Diagnosis. Littleton,
Mass.: PSG Pub. Co., 1987; Tohen M et al: Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled
study. The Olanzapine HGGW Study Group. Arch Gen Psychiatry 57:841, 2000; Tohen M et al:
Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry 159:1011, 2002; Tohen M et al:
Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry
156:702, 1999; Woo BK et al: Unrecognized medical disorders in older psychiatric inpatients in a senior behavioral
health unit in a university hospital. J Geriatr Psychiatry Neurol 16:121, 2003; Zajecka JM et al: A comparison of
the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin
Psychiatry 63:1148, 2002.
Educational Objectives
The goal of this program is to improve management of bipolar disorder and diagnosis of underlying medical causes
for psychiatric symptoms in the elderly. After hearing and assimilating this program, the clinician will be better able
to:
| 1. Describe how pharmaceutical companies design medication trials to support their applications for Food and
Drug Administration (FDA) approval of those medications.
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| 2. Discuss how lithium works in treating bipolar disorder.
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| 3. Review the data on the efficacy of several categories of medications used in treating bipolar disorder.
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| 4. Describe physiologic changes in the elderly that make them more likely to manifest psychiatric symptoms in
the presence of medical disease and medications.
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| 5. Enumerate some pitfalls to be avoided when diagnosing psychiatric symptoms in the elderly with medical illnesses.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
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. Dubovsky is a consultant for Bioval, a principle investigator for Organon, Pfizer, Solvay, and UCB Pharma, and
a speaker for Organon. Dr. Pies and the planning committee reported nothing to disclose.
Acknowledgements
Drs. Dubovsky and Pies were recorded at Helpful Highlights from Heartsome Heedful Headliners, presented November
2-3, 2007, in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public Health
and the Madison Institute of Medicine, Inc. The Audio-Digest Foundation thanks the speakers and the sponsors for
their cooperation in the production of this program.
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