Psychopharmacology

Risperidone Versus Haloperidol in the Treatment of Schizophrenia in Elderly Subjects –
Effect on Cognition of Paroxetine Versus Lorazepam in the treatment of Anxiety: A Pilot Study –
Duloxetine Versus Placebo In The Treatment Of Elderly Patients With Major Depressive Disorder

Risperidone Versus Haloperidol in the Treatment of Schizophrenia in Elderly
Subjects

This is a pilot investigation to compare risperidone versus haloperidol
for the treatment of symptoms of schizophrenia and schizoaffective disorder
in elderly patients over an 12-week period.

Subjects will be randomized to either risperidone or haloperidol. The
double-blind treatment will consist of capsules which will be identical
in appearance and which will contain either risperidone 0.5 mg or haloperidol
1.0 mg. Study medication will be adjusted according to clinical response.
Study visits will take place at screening, baseline, and at weeks 2,3,4,5,7,9,11,and
13. Additional visits may take place as appropriate. Cognitive functioning
will be evaluated at baseline and at week 13. The total trial duration
is 13 weeks (1 week washout, 12 weeks double-blind treatment).

Subjects who meet all of the following criteria are eligible for this
trial:

Diagnosis of schizophrenia or schizoaffective disorder (DSM-IV).
Aged > 65.
Inpatients or outpatients. Nursing home patients may be included
in the study.
Subject and/or legal guardian or representative (if assigned) has
signed the informed consent form.

Subjects meeting one or more of the following criteria cannot be selected:

A DSM-IV Axis I diagnosis other than schizophrenia or schizoaffective
disorder.
DSM-IV diagnosis of substance abuse or dependence within 3 months
prior to selection.
Major depressive episode according to the DSM-IV criteria within
6 months of the screening visit.
A Mini-Mental Status Examination score of < 10.
Documented disease of the central nervous system including tumor,
Alzheimer’s disease, Huntington’s disease, history of brain trauma resulting
in documented cognitive impairment, chronic infection, neurosyphilis.
A subject with a previous history of stroke may be included in the study
provided s/he has recovered with no cognitive impairment or other residual
effects which would affect the study assessments.
Hepatic, renal or gastrointestinal disease of sufficient degree to
interfere with the excretion, absorption and/or metabolism of trial medication.
Subjects with clinical signs of liver disease should be excluded from
the study.
Acute (e.g., infection), unstable (e.g., labile hypertension, unstable
angina), significant or untreated medical illness. Subjects with diastolic
blood pressure >95 mmHg at screening should be treated and stabilized
for thirty days before randomization.
Subjects with chronic urinary retention and/or clinically significant
prostatic hypertrophy, paralytic ileus or related conditions, which in
the opinion of the investigator may be exacerbated by the anticholinergic
effects of haloperidol.
Subjects with QTc interval of >500 msec. A subject whose screening
ECG shows a QTc interval >500 msec may be re-evaluated one week later.
If the second ECG shows a QTc interval > 500 msec the subject should
not be enrolled. If the QTc interval is < 500 msec, the subject may be enrolled, provided all the other inclusion/exclusion criteria are met.
History of treatment with risperidone (prescribed for treatment refractory
schizophrenia) for more than 4 consecutive weeks.
Treatment with haloperidol within 28 days prior to screen.
Participation in an investigational drug trial in the 28 days prior
to the screening visit.
History of severe drug allergy or hypersensitivity.
Known sensitivity to risperidone or haloperidol.
Subjects known to be unresponsive to either risperidone or haloperidol
in the opinion of the investigator.
History of neuroleptic malignant syndrome.
Presence or history of tardive dyskinesia.

Primary Investigator

Carl Salzman, MD

Co-Investigators

James Beck, M.D., Ph.D.
Stephen Pinals, M.D.
Alan I. Green, M.D.
Larry Seidman, Ph.D.
Jonathan Shack, M.D.
Eileen Wong, M.D.
Alexandra L. Accardi, M.D.
Marc Frader, M.D.

Contact Chari Cohen at 617-626-9419 for more information about this study.

Effect on Cognition of Paroxetine Versus Lorazepam in the treatment of
Anxiety: A Pilot Study

This is a pilot study to determine whether a large prospective study
comparing the effects of an SSRI (paroxetine) and a benzodiazepine (lorazepam)
is feasible and worthwhile. The study arises out of the observation that
an increasing number of patients with generalized anxiety disorder are
receiving SSRI antidepressants for the treatment of their anxiety symptoms.
The use of SSRI antidepressants avoids the development of dependence,
potential withdrawal symptoms, and cognitive impairment. However it is
not clear whether SSRI antidepressants are as effective as benzodiazepines
for the treatment of GAD since no “head-to-head” study comparing
the two classes of medications has ever been conducted. Benzodiazepines
are known to be effective treatments for anxiety, and have the benefit
of no sexual side effects. This pilot study, therefore, will compare in
a preliminary way anxiety reduction, as well as side effects, specifically
sexual dysfunction and cognitive impairment. This pilot study is being
conducted with particular interest regarding the elderly anxious population.
The use of SSRI antidepressants might be preferable to the use of benzodiazepines
in the elderly since benzodiazepines are known to impair cognition in
the elderly, and the sexual dysfunction of SSRI antidepressants may be
less relevant in an elderly population.

Inclusion Criteria

DSM-IV criteria for generalized anxiety with or without social
anxiety disorder
Exclusion Criteria:
Schizophrenia, bipolar disorder, major depressive disorder,
OCD, panic disorder
Unstable medical illness that would contraindicate participation
in the study
Active or past history of alcohol or drug abuse
Concurrent psychotropic medication
Concurrent cigarette smoking

Primary Investigator

Carl Salzman, MD

Primary contact

Chari Cohen

Phone: 617-626-9419

Duloxetine Versus Placebo In The Treatment Of Elderly Patients With Major
Depressive Disorder

This protocol is a multicenter, parallel, double-blind, placebo-controlled
study of
approximately 300 enrolled elderly patients (>65 years of age) who
meet the DSM-IV (APA 1994) diagnostic criteria for MDD. Patients who meet
entry criteria in a 1-week screening phase (Study Period I) will be randomly
assigned within each study site to receive either duloxetine 60mg QD or
placebo. Following the screening phase, patients will be treated in a
double-blind manner for 9 weeks in the acute treatment phase (Study Period
II). Patients will then enter into a 1-week, double-blind, discontinuation
phase (Study Period III), at which time the dosage of the drug will be
tapered.

The primary objective of this protocol is to compare the efficacy of
duloxetine with placebo on cognition and depression in elderly patients
(>65 years of age) diagnosed with MDD.

The population for this study includes elderly patients (>65 years
of age) who meet the DSM-IV diagnostic criteria for MDD.

Patients are eligible to be included in the study only if they meet all
of the following criteria:

Are male or female outpatients at least 65 years of age.
Sign the informed consent document.
Meet criteria for major depression, as defined by DSM-IV.
Have a HAM-D17 total score >18 at Visits 1 and 2.
Have a Mini-Mental State Exam (MMSE) score >20 with or without
mild dementia.
Have a degree of understanding such that the patient can communicate
intelligibly with the investigator and study coordinator.
Are judged to be reliable and agree to keep all appointments for
clinic visits, tests, and procedures required by the protocol and are
able to swallow all required medication without opening or crushing.

Patients will be excluded from the study if they meet any of the following
criteria:

Are investigator site personnel directly affiliated with the study,
or are immediate family of investigator site personnel directly affiliated
with the study. Immediate family is defined as a spouse, parent, child,
or sibling, whether biological or legally adopted.
Are employed by Lilly (that is, employees, temporary contract workers,
or designees responsible for the conduct of the study). Immediate family
of Lilly employees may participate in Lilly-sponsored clinical trials,
but are not permitted to participate at a Lilly facility. Immediate family
is defined as spouse, parent, child or sibling, whether biological or
legally adopted.
Have received treatment with a drug within the last 30 days that
has not received regulatory approval at the time of study entry.
Are persons who have previously completed or withdrawn from this
study or any other study investigating duloxetine. (Note: Patients that
have been previously screened for a duloxetine study other than this study
and never received study drug will be eligible for this study if they
meet all current entry criteria).
Have any current and primary Axis 1 disorder other than MDD, including,
but not limited to, dysthymia or psychotic depression.
Have any previous diagnosis of bipolar disorders, schizophrenia,
or other psychotic disorders.
Have any anxiety disorder as primary diagnosis within the past year
(including panic disorder, obsessive-compulsive disorder, posttraumatic
stress disorder, generalized anxiety disorder, and social phobia but excluding
specific phobias).
Have organic mental disorder, moderate to severe dementia, or mental
retardation diagnosis.
Are judged to be at serious risk as judged by the investigator.
Have a history of substance abuse or dependence within the past
year (drug categories defined in the DSM-IV), excluding nicotine and caffeine.
Have a positive urine drug screen for any substances of abuse. Note:
if the patient has a positive drug screen for a substance at Visit 1,
a retest may be performed prior to Visit 2, if in judgment of the investigator,
there is an acceptable explanation for the positive result. If the retest
is positive, the patient will be excluded.
Have a serious or unstable medical illness, psychological condition,
or clinically significant laboratory abnormality that in the opinion of
the investigator would compromise participation in this study or be likely
to lead to hospitalization during the course of the study.
Have at Visit 1 an ALT, AST, or GGT >1.5 times upper limit of
normal, based on Lilly reference ranges.
Are taking any excluded medication listed in Protocol Attachment
HMBV.3 within 7 days prior to Visit 2.
Have had treatment with a monoamine oxidase inhibitor (MAOI) within
14 days prior to visit 2 or have the potential need to use an MAOI within
2 weeks of discontinuation of study drug.
Have had treatment with fluoxetine within 30 days prior to visit
2.
Have frequent and/or severe allergic reactions to multiple medications,
or known allergic reactions to any of the study drugs.
Have abnormal thyroid-stimulating hormone (TSH) concentration. Note:
Patients previously diagnosed with hyperthyroidism or hypothyroidism who
have taken a stable dose of thyroid supplement for at least the past 6
months, have medically appropriate TSH concentrations, and are clinically
euthyroid are allowed.
Have discontinued thyroid replacement therapy within the previous
3 months.
Have not had a previous episode of major depression.
Have had electroconvulsive therapy (ECT) or transcranial magnetic
stimulation (TMS) within the past year.

This study takes place at the Mount Auburn Hospital in Cambridge,
MA

Carl Salzman, MD (Primary Investigator)
Joseph D’Afflitti, MD (Subinvestigator)
Michelle Wiersgalla, MD (Subinvestigator)
Barbara Yee, RN
Maureen Rakiey, RN
Chari Cohen, BA (Study Coordinator)
Mark Stoia

For information regarding this study, please call Chari Cohen at 617-626-9419
or the Clinical Trials Center at Mount Auburn Hospital at 617-499-5774