Pharmacology of Cognition in Schizotypal Personality Disorder

Schizotypal personality disorder is a psychiatric condition that is characterized by
deficiencies in interpersonal relationships and disturbances in thought patterns,
appearance, and behavior. This disorder is different from schizophrenia. While some of the
symptoms of the two disorders are similar, such as the tendency to have unusual beliefs and
behaviors, people with schizotypal personality disorder do not experience hallucinations and
are not significantly disconnected from reality, both of which are signature symptoms of
schizophrenia. Guanfacine is a drug that is often used to treat high blood pressure and
attention deficit hyperactivity disorder. There is evidence that guanfacine enhances
cognition and diminishes impulsivity. This study will determine the effectiveness of
guanfacine in improving symptoms of schizotypal personality disorder.

Participants in this 6-week, double-blind study will be randomly assigned to receive either
guanfacine or placebo. Participants receiving guanfacine will remain on the drug for the
duration of the study. The other participants will receive placebo for the duration of the
study. Guanfacine dosages will not exceed 2 mg per day. All participants will report to the
study site weekly for assessments of vital signs, study compliance, medication side effects,
and psychological symptoms. Additional cognitive testing will be performed at week 6. Upon
study completion, patients will return for a follow-up assessment.

Inclusion Criteria:

- Subjects must be male or female

- Medically and neurologically healthy (Medically healthy means that the patient does
not have a major or partially treated medical condition that based on the judgment of
the research clinician would either put the patient at increased risk and/or affect
our findings. Common conditions include: high blood pressure, diabetes, uncontrolled
asthma or COPD, abnormal heart rhythm, chronic viral infections. Neurologically
healthy means that the patient has not experienced brain injury or head trauma
associated with prolonged (e.g., > 10 minutes) loss of consciousness, seizures or
other conditions based on the research clinician's judgment would either put the
patient at increased risk and/or affect our findings.)

- Between 18 and 60 years of age

- Patients must also be medication free (at least 2 weeks) while participating in
guanfacine, except for the following medications: NSAIDS (eg, Advil), Tylenol,
Levothyroxine (if on stable dose for 1 month, no symptoms of hypothyroidism and
normal thyroid labs), Non-centrally acting antihistamines, H2 blockers (eg, Zantac),
PPIs (eg, Prilosec, Prevacid). Research physician will make judgment on case-by-case
basis based on risk to subject, and potential confounding effect on data validity.

- Subjects in the SPD group must meet DSM-IV criteria for Schizotypal Personality
Disorder.

- Subjects in the AvPD group must meet DSM-IV criteria for Avoidant Personality
Disorder and not meet criteria for schizotypal, paranoid, and schizoid personality
disorder. In addition, the AvPD group must have fewer than 2 schizotypal traits.

Exclusion Criteria:

- Subjects may not have a significant medical illness (ie, insulin dependent diabetes,
gastric/duodenal ulcer), or significant neurological illness (ie epilepsy, CMS, CVA,
focal neurological lesion).

- Any cardiovascular condition that, based on the research clinician's judgment (which
includes cardiological consultation), would put the participant at increased risk
will be considered an exclusion criteria. This would certainly include evidence by
history or exam of heart block, tachyarrhythmia, angina, ventricular hypertrophy,
those taking antihypertensives. Blood pressure parameters will be a >25% decrease in
mean arterial systolic blood pressure from baseline, an orthostatic decrease in
systolic blood pressure of 20 mm Hg and/or in diastolic blood pressure of 10 mm Hg,
and heart rate parameter will be below 55 bpm.

- Participants are also excluded if they are more than 40% above ideal body weight. The
weight limit helps insure that standard doses of guanfacine will not be given to
patients who are extremely overweight who might then receive a lower concentration of
these drugs in their central nervous system.

- Subjects must also have a corrected or uncorrected visual acuity of 20/40 or better.

- All participants meeting DSM IV criteria for any current or past history of sustained
IV-substance dependence are excluded from the study.

- Participants must be free of substance abuse for at least six months.

Healthy Controls:

Inclusion Criteria:

- Healthy control subjects will be selected according to criteria noted in methods, and
in age distribution comparable to our patients.

- Healthy controls will be matched to patients on gender and parental socioeconomic
status.

- Healthy controls must be male or female between the ages of 18 and 60.

Exclusion criteria:

- for medical illness are identical to those of patients

- must not meet criteria for a current or lifetime DSM-IV diagnosis of bipolar
disorder, schizophrenia, schizoaffective disorder, or any Axis II disorder.

- a current Axis I or II diagnosis or a family history of psychotic disorder will also
be excluded. However, to avoid a group of HC's too highly groomed and
unrepresentative of the general population we will not exclude HC subjects meeting
criteria for a past Axis I diagnosis, such as adjustment disorder, dysthymic
disorder, depressive disorder not otherwise specified, specific phobia, and sleep
disorders. In addition subjects meeting criteria for a non-IV substance abuse
disorder more than 6 months prior to enrollment will not be excluded.