ALZHEIMER'S DISEASE/BORDERLINE PERSONALITY DISORDER
From the 11th Annual Psychopharmacology Update, presented by the American Psychiatric Association and the
Nevada Psychiatric Association
| RATIONALIZING THERAPIES IN ALZHEIMER’S DISEASE —George T. Grossberg, MD, Samuel W.
Fordyce Professor and Director, Geriatric Psychiatry, St. Louis University School of Medicine, St. Louis,
MO
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| Introduction: at autopsy, rare to find patients with only vascular disease in brain; most often mixed with
Alzheimer’s disease (AD); in life, those with AD and vascular disease tend to decline more rapidly and
to have more significant symptomatology; amyloid neuritic plaques and neurofibrillary tangles seen in
normal aging; diagnosis of AD depends on quantity and location of plaques and tangles
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| Neuroimaging: positron emission tomography (PET) most sensitive for picking up early changes (decreased
metabolic activity, particularly in temporoparietal region) of AD in living patients, but currently
not approved by Medicare
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| Pathophysiologic hypothesis of AD: glutamate thought to cause cell damage and loss through excitotoxic
mechanism; glutamate not excessive in patients with AD, but becomes aberrant and develops excitotoxic
profile; deposition of β-amyloid plaques and neurofibrillary tangles contribute to cell loss; decrease in
cholinergic neurotransmission is “major neurochemical accompaniment of AD and other dementias”
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 | Inflammation and mitochondrial dysfunction: may have roles, but not yet fully elucidated; controlled
prospective trials showed no benefit with anti-inflammatory medications
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| Treatment goals: maintain quality of life; maximize function; stabilize cognition; treat mood and behavior
problems; ease caregiver burden; establish realistic expectations for treatment
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| Treatment considerations: current guidelines from American Academy of Neurology recommend that all
patients with AD begin treatment at time of diagnosis; well-established rationale for giving cholinesterase
inhibitors to patients with mild to moderate AD; well-established rationale for giving memantine to
patients with moderate to severe AD; patients with severe AD shown to benefit from treatment
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| Neurotransmitter basis for treatment: acetylcholine and glutamate important in learning and memory; in
AD, cholinergic neurons lost and excessive or erratic glutamate impairs learning and can cause neuronal
toxicity; theoretically, increasing available acetylcholine may maintain or improve function, and normalizing
glutamatergic neurotransmission may maintain or improve function and prevent neurotoxicity
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| Cholinesterase inhibitors (ChEIs): tacrine, donepezil, galantamine, and rivastigmine currently approved by
Food and Drug Administration (FDA), but tacrine rarely used; monotherapy with ChEI standard treatment;
side effects of ChEIs include nausea, vomiting, diarrhea, anorexia, weight loss, dizziness, leg cramps,
urinary incontinence, insomnia, and nightmares; in trials, improvement seen in cognition, global measures,
and activities of daily living (ADLs) in patients with mild to moderate disease
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| Memantine: N-methyl-D-aspartate (NMDA)-receptor antagonist; not approved by FDA for use in mild
or early-stage AD, but at least 3 trials have looked at its use there; US trial showed significant benefits
and European trial had mixed results; in second US trial, patients already taking ChEI randomized to
addition of memantine or placebo; some benefit shown, but did not reach statistical significance; at 20
mg/day, safety profile similar to that of placebo; does not have gastrointestinal side effects associated
with ChEIs; potential for decreased renal clearance with drugs that undergo tubular secretion; avoid
use with other NMDA-receptor antagonists; no drug interactions with ChEIs; if patient has moderate
renal impairment, decrease dose; not recommended in patients with severe renal impairment
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| Functionality: different ADLs lost at different stages of AD; higher-level activities (eg, handling money)
lost first; more basic ADLs (eg, bathing, grooming, toileting) begin to be lost in middle stage and continue
in later stage; ChEIs shown to improve or stabilize functionality, even in middle or later stages of
AD
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| Behavior: problem behaviors, especially agitation and aggressiveness, most frequent cause of institutionalization;
so far, only 1 study done to assess impact of ChEIs on behavior, but it suggested they may help
prevent emergence of problem behaviors; another study showed that individuals on donepezil ≥2 yr at
start of study able to be kept at home average of 21 mo longer than those who had limited exposure to
donepezil or placebo
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| Long-term studies: show that people who stay on ChEIs, memantine, or combination thereof over time do
better than people on nothing or on placebo; in nursing home, patients on drugs need fewer antipsychotics
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| Other treatment options for AD: many being tried; Robert Wood Johnson Foundation funding “Green
House” trials in which patients placed in small group homes rather than nursing homes; other concepts
also try to modify environment to treat or to prevent problem behaviors; use of bright light being tested
to treat sundowning
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| Other pharmacologic therapies: ChEIs and memantine seem to have greatest impact on behaviors; however,
difficult behaviors may suggest use of antipsychotic agents; antipsychotics have small but real increased
risk for stroke and mortality; these risks should be discussed thoroughly with patient’s family
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| When to stop drugs: when patient at stage of AD not amenable to starting pharmacotherapy, ie, if patient
no longer has meaningful quality of life that can be preserved or stabilized
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| Conclusions: acetylcholine and glutamate current foci for pharmacologic treatment; controlled data support
use of ChEIs in all stages of AD, but approved by FDA only in mild to moderate disease; controlled
data support use of memantine in all stages of AD, but approved by FDA only in severe disease; controlled
data support combination of memantine and ChEI in moderate to severe disease; current antidementia
therapies may have beneficial effect on cognition, behavior, and ADLs in AD; current therapies
may decrease caregiver burden and delay institutionalization of patients with AD
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| PHARMACOTHERAPY UPDATE: BORDERLINE PERSONALITY DISORDER (BPD)—S. Charles
Schulz, MD, Professor and Head, Department of Psychiatry, University of Minnesota Medical School,
Minneapolis
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| Caveat: no medications discussed by speaker approved by FDA for treatment of BPD
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| Therapeutic approach to BPD: get to know patients and identify areas where they have difficulty, aiming
therapy at that area; for example, start antidepressant for depression, mood stabilizer for moodiness, or
antipsychotic medication for cognitive difficulty
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| Selective serotonin reuptake inhibitors (SSRIs): although initially used to relieve depression, studies
show relatively broad reduction of symptoms of BPD; in recent study of fluvoxamine, first 6 wk of therapy
showed statistically significant advantage for fluvoxamine, especially in reducing rapid mood shifts;
over next 24 wk, reduction seen in mood, anger, and impulsivity; another trial showed greater response
to 80 mg/day of fluoxetine than to placebo, suggesting that larger doses of SSRIs may be needed in BPD;
other trials show efficacy of sertraline
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| Clonidine: “aversive inner tension” causes self-destructive behaviors (eg, self-cutting); one study found
reduced aversive inner tension and urge to cut after each of 2 doses of oral clonidine; further studies
needed, including placebo-controlled studies
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| Mood-stabilizing anticonvulsants: reduce moodiness and may reduce aggressiveness; divalproex—in
study of women with BPD and bipolar II disorder, divalproex better than placebo in reducing interpersonal
sensitivity, anger, and hostility and in reducing overall aggression as measured on Modified Overt Aggression
Scale (OAS-M); preliminary study of divalproex vs placebo showed no significant differences between
groups, but study small (16 patients) and dropout rate high; authors think larger controlled trials needed; in
study of trait impulsivity and state aggression, specific affective symptoms did not influence treatment outcome,
suggesting that divalproex has direct effect on aggression rather than one mediated by improvement
in affective instability; oxcarbazepine—placebo-controlled trial with 17 patients showed statistically significant
reduction in symptoms and in Brief Psychiatric Rating Scale (BPRS); more trials needed
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| Atypical antipsychotics: quetiapine—case series showed some improvement in first 4 wk and statistically
significant reduction in symptoms in last 4 wk; risperidone—trial showed improvement in symptoms,
but because patients given concurrent dialectical behavior therapy (DBT), unable to separate improvement
due to medication from improvement due to DBT; olanzapine—in study of 28 women with BPD,
olanzapine significantly superior to placebo on all symptom ratings, except depression; modest weight increase
seen, but no movement disorders; other studies also showed improvement in symptoms as early as
4 wk and broad effect on symptoms; olanzapine and fluoxetine combination (OFC)—45 patients with BPD
without major depression randomized to fluoxetine alone, olanzapine alone, or fixed-dose combination;
olanzapine alone and OFC significantly superior to fluoxetine alone on OAS-M and Montgomery-Asberg
Depression Rating Scale (MADRS), although patients on fluoxetine alone showed reduction in impulsivity,
aggression, and depression; ziprasidone—only 1 study available, used ziprasidone in
emergency department in patients taking other drugs; “it’s not the sort of data that would lead one to use
it, but at least it’s a start”; aripiprazole—no studies; quetiapine—preliminary study showed decrease in
symptoms, but authors point out study does not support American Psychiatric Association (APA) guidelines;
more studies needed
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| In the works: new outcome measures being explored that look at things other than symptoms; studies under
way to see what medicines, combinations of medicines, and cognitive rehabilitation programs in conjunction
with medicines are most useful in helping with social and functional outcomes; one group
exploring whether medicines can improve scores on neuropsychologic tests; in one study, patients who
received olanzapine while getting DBT did better than those who received placebo and DBT
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| What is being treated? responsiveness to most medications good, suggesting polypharmacy may not be
necessary; one group notes that typical antipsychotic medications show broad spectrum of efficacy in
BPD
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| Next steps: larger placebo-controlled trials and comparison studies; measuring new parameters such as
neuropsychology or brain imaging; testing combinations of medications and psychosocial treatments
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Educational Objectives
| The goal of this program is to educate the listener about rationalizing therapies in Alzheimer’s disease (AD) and pharmacotherapy
in borderline personality disorder (BPD). After hearing and assimilating this program, the clinician will
be better able to:
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| 1. Explain the hypothetical role of glutamate and acetylcholine in AD.
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| 2. List the medications currently approved by the Food and Drug Administration (FDA) for treatment of AD.
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| 3. Reduce caregiver burden and delay institutionalization of patients with AD.
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| 4. Describe the current approach to treatment of patients with BPD.
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| 5. Discuss the outcomes of trials that used various classes of medications to treat BPD.
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Discussed on This Program
Clonidine hydrochloride [Catapres, Duraclon]
Divalproex sodium [Depakote, Depakote ER]
Donepezil hydrochloride [Aricept, Aricept ODT]
Fluoxetine hydrochloride [Prozac, Sarafem]
Fluvoxamine maleate
Galantamine hydrobromide [Reminyl, Razadyne]
Memantine hydrochloride [Namenda]
Olanzapine [Zyprexa]
Olanzapine and fluoxetine hydrochloride [Symbyax]
Oxcarbazepine (oxycarbamazepine) [Trileptal]
Quetiapine fumarate [Seroquel]
Risperidone [Risperdal]
Rivastigmine tartrate [Exelon]
Sertraline hydrochloride [Zoloft]
Ziprasidone hydrochloride [Geodon]
Suggested Reading
Bellino S, Paradiso E, Bogetto F: Oxcarbazepine in the treatment of borderline personality disorder: a pilot study.
J Clin Psychiatry 66:1111, 2005; Bogenschutz MP, George Nurnberg H: Olanzapine versus placebo in the treatment
of borderline personality disorder. J Clin Psychiatry 65:104, 2004; Desai AK, Grossberg GT: Diagnosis and
treatment of Alzheimer’s disease. Neurology 64(12 Suppl 3):S34, 2005; Desai AK, Grossberg GT: Recognition
and management of behavioral disturbances in dementia. Prim Care Companion. J Clin Psychiatry 3:93, 2001; Desai
AK, Grossberg GT: Rivastigmine for Alzheimer’s disease. Expert Rev Neurother 5:563, 2005; Frankenburg
FR, Zanarini MC: Divalproex sodium treatment of women with borderline personality disorder and bipolar II disorder:
a double-blind placebo-controlled pilot study. J Clin Psychiatry 63:442, 2002; Gauthier S et al: Strategies for
continued successful treatment of Alzheimer’s disease: switching cholinesterase inhibitors. Curr Med Res Opin 19:707,
2003; Grossberg GT: Alzheimer’s disease pathways to practice: assessing diagnosis and outcome measures. CNS
Spectr 10(11 Suppl 18):5, 2005; Grossberg GT: Effect of rivastigmine in the treatment of behavioral disturbances associated
with dementia: review of neuropsychiatric impairment in Alzheimer’s disease. Curr Med Res Opin 21:1631,
2005; Grossberg GT: Rationalizing therapeutic approaches in Alzheimer’s disease. CNS Spectr 10(11 Suppl 18):17,
2005; Grossberg GT: The ABC of Alzheimer’s disease: behavioral symptoms and their treatment. Int Psychogeriatr
14(Suppl 1):27, 2002; Hollander E et al: Impact of trait impulsivity and state aggression on divalproex versus placebo
response in borderline personality disorder. Am J Psychiatry 162:621, 2005; Markovitz PJ et al: Fluoxetine in
the treatment of borderline and schizotypal personality disorders. Am J Psychiatry 148:1064, 1991; Pascual JC et al:
Ziprasidone in the acute treatment of borderline personality disorder in psychiatric emergency services. J Clin Psychiatry
65:1281, 2004; Philipsen A et al: Clonidine in acute aversive inner tension and self-injurious behavior in female
patients with borderline personality disorder. J Clin Psychiatry 65:1414, 2004; Rinne T et al: SSRI treatment of borderline
personality disorder: a randomized, placebo-controlled clinical trial for female patients with borderline personality
disorder. Am J Psychiatry 159:2048, 2002; Salzman C et al: Effect of fluoxetine on anger in symptomatic
volunteers with borderline personality disorder. J Clin Psychopharmacol 15:23, 1995; Schulz SC et al: Olanzapine
safety and efficacy in patients with borderline personality disorder and comorbid dysthymia. Biol Psychiatry 46:1429,
1999; Snowdon DA et al: Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA
277:813, 1997; Tariot PN et al: Memantine Study Group. Memantine treatment in patients with moderate to severe
Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291:317, 2004; Zanarini MC,
Frankenburg FR, Parachini EA: A preliminary, randomized trial of fluoxetine, olanzapine, and the olanzapine-
fluoxetine combination in women with borderline personality disorder. J Clin Psychiatry 65:903, 2004; Zanarini
MC: Update on pharmacotherapy of borderline personality disorder. Curr Psychiatry Rep 6:66, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Grossberg disclosed that he is a consultant to or on the advisory board of Forest, Synthelabo, Orgenon, Novartis,
Eli Lilly & Co., Pfizer, and Janssen; he has grant/research support from Abbott, Bristol-Myers-Squibb, Pfizer, Janssen,
ONO, Novartis, Wyeth, and Cyberonics. Dr. Schulz disclosed that he is a consultant to or on the advisory board
of AstraZeneca and Eli Lilly & Co.; he receives grant/research support from Abbott, AstraZeneca, and Eli Lilly &
Co,; and he is on the Speakers’ Bureau of AstraZeneca.
Drs. Grossberg and Schulz were recorded at the 11th Annual Psychopharmacology Update, held February 16-19,
2006, in Las Vegas, NV, and sponsored by the American Psychiatric Association and the Nevada Psychiatric Association.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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