p11 Protein Levels in Patients With Major Depressive Disorder Treated With Citalopram

Major depressive disorder (MDD) is a serious, debilitating, life-shortening illness that
affects many persons of all ages and backgrounds. While treatments are effective for a
significant portion of patients with MDD, progress in developing more effective treatments is
lagging. Furthermore, with regards to existing antidepressant medications, there are yet no
reliable predictors of the likelihood of remission, response or non-response with an initial
trial of an antidepressant medication. Identifying factors that are likely to predict
response would have the advantage of personalizing treatment to a particular individual; that
is selecting the antidepressant medication that is most likely to give the greatest
probability of having a favorable outcome.

The serotonin system has been implicated in the pathophysiology of depression and mechanism
of action of existing effective antidepressant treatments. Fourteen different serotonin
receptors have been identified to date. One of them, 5-HT1B, plays an important role in
regulating serotonin neurotransmission. Recently, p11 (a member of the S100 family of
proteins) was found to interact with 5-HT1B receptors (Svenningsson et al 2006; Svenningsson
and Greengard 2007). p11 mRNA levels are markedly reduced in the forebrain in helpless
H/Rouen mice and the level of p11 mRNA was down-regulated in the anterior cingulate cortex
from depressed patients. p11 mRNA is distributed in an anatomical pattern that closely
resembled that of 5-HT1B receptor mRNA, including cortex, hippocampus, hypothalamus and raphe
nuclei. Chronic administration of the antidepressants imipramine, tranylcypromine, and
citalopram significantly increase the level of p11 in cortex. Finally, we have found that
chronic treatment with fluoxetine increases p11 in peripheral mononuclear cells in monkeys.

We will now study whether the blood cell levels of p11 differ between healthy individuals and
patients suffering from unipolar depression. Moreover, we will study whether the levels of
p11 are affected by treatment with the selective serotonin reuptake inhibitor, citalopram.
Complementary work will continue at other laboratories to better characterize the role of p11
in the pathophysiology of depression (e.g., animal studies, post-mortem studies).

In addition, we will also acquire a battery of magnetic resonance imaging (MRI) scans in a
subset of 45 more homogeneous depressed subjects, and 45 matched healthy controls at baseline
and at 8 weeks. There is a growing body of evidence implicating morphometric and physiologic
abnormalities, measureable by MRI, in the pathophysiology of major depressive disorder. We
will assess both baseline differences between depressed subjects and healthy controls,
treatment effects, and search for possible MRI markers predicting treatment response.

This is an open label study which will be performed at the National Institute of Mental
Health. In all, 82 adult subjects with major depressive disorder, between the ages of 18 and
65 years, will be recruited from the community. In addition, we will perform p11 measurements
in blood cells from 64 healthy control subjects.

- INCLUSION CRITERIA:

CRITERIA FOR INCLUSION OF DEPRESSED PATIENTS:

- age 18-65 years

- written informed consent completed (consent-incapacitated subjects will not be
eligible)

- score 20 or higher on the Montgomery-Asberg Depression Rating Scale (MADRS)

- meets DSM-IV criteria for chronic or recurrent nonpsychotic MDD

- patients who are on non-excluded concomitant medications.

- no more than 3 failed antidepressant treatments within the current major depressive
episode

- no alcohol use (last 7 days)

ADDITIONAL CRITERIA FOR INCLUSION OF DEPRESSED PATIENTS FOR MRI IMAGING:

- age 18 55 years

- subjects must have either a family history of mood disorders, or have a history of

multiple major depressive episodes

- age of onset of depressive symptoms less than 45 years

- no history of past alcohol or substance dependence (excluding nicotine) or alcohol or
substance abuse (excluding nicotine) within the past year.

- no use of benzodiazepines within 2 weeks of either MRI scan

CRITERIA FOR INCLUSION OF HEALTHY CONTROL SUBJECTS:

- age 18-65 years

- written informed consent completed

- no current or past diagnosis of axis I psychiatric disorder (DSM-IVTR)

- no alcohol use (last 7 days)

- physically healthy

ADDITIONAL CRITERIA FOR INCLUSION OF HEALTHY CONTROL SUBJECTS FOR MRI IMAGING:

- age 18 55 years

- no history of past alcohol or substance dependence (excluding nicotine) or alcohol or
substance abuse (excluding nicotine) within the past year.

EXCLUSION CRITERIA:

CRITERIA FOR EXCLUSION OF DEPRESSED PATIENTS:

- history of bipolar disorder (I, II, or NOS) (lifetime)

- history of schizophrenia

- history of schizoaffective disorder or

- psychosis NOS (lifetime)

- history of anorexia nervosa or bulimia nervosa (lifetime)

- current primary obsessive-compulsive disorder (OCD) or current post traumatic stress
disorder (PTSD) whose onset preceded the onset of Major Depressive Disorder

- history of clear-cut intolerability to the study medication

- lack of response to an adequate trial of the study medication (citalopram) in the
current or past episodes of MDD

- did not respond to 7 or more sessions of ECT in the current episode of MDD

- Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory,
cardiovascular (including ischemic heart disease), endocrinologic, neurologic,
immunologic, or hematologic disease.

- has general medical condition which contraindicates the use of the study medication

- is on concomitant medication which contraindicates the use of the study medication

- requires immediate hospitalization for psychiatric disorder

- requires antipsychotic medications or mood stabilizers

- Non-postmenopausal (less than 2 years since last period) females of childbearing
potential who are sexually active and who are not using adequate (hormonal, double
barrier, surgical) contraception, or who are pregnant or breast feeding

- patients currently taking any of the exclusionary medications detailed in protocol
(including antipsychotic medications, anticonvulsant medications, antidepressant
medications, mood stabilizers, central nervous system stimulants) in the 2 weeks prior
to Study Period II.

- patients taking thyroid medication for hypothyroidism may be included if they have
been stable on the medication for greater than 3 months

- patients can participate in a modality of psychotherapy that is not targeting the
symptoms of depression (e.g., supportive therapy, marital therapy)

- therapy that is depression specific, such as Cognitive Therapy (CT) or Interpersonal
Psychotherapy of Depression (IPT) is not allowed during participation

- subjects must be fluent in English and have the capacity to understand the nature of
the study and sign the written informed consent.

- current alcohol dependence or abuse (last 3 months)

- patient has a prolonged QTc (greater than or equal to 450 msec), as shown on ECG

- Current NIMH employee/staff or their immediate family member.

ADDITIONAL CRITERIA FOR EXCLUSION OF DEPRESSED PATIENTS FOR MRI IMAGING:

- subjects meeting general exclusion criteria for MRI scanning (e.g. implanted cardiac
pacemaker, intraocular metal) will be excluded from the MRI procedures only.

- subjects with structural lesions visible on MRI will be excluded from further MRI
procedures

- subjects with diabetes or hypertension will be excluded

CRITERIA FOR EXCLUSION OF HEALTHY CONTROL SUBJECTS:

- subjects currently taking any of the exclusionary medications detailed in protocol in
the 2 weeks prior to evaluation

- current alcohol dependence or abuse (last 3 months)

- history of major depression or bipolar disorder in any first degree relative

ADDITIONAL CRITERIA FOR EXCLUSION OF HEALTHY CONTROL SUBJECTS:

- subjects meeting general exclusion criteria for MRI scanning (e.g. implanted cardiac
pacemaker, intraocular metal) will be excluded from the MRI procedures only.

- subjects with structural lesions visible on MRI will be excluded from further MRI
procedures

- subjects with diabetes or hypertension will be excluded