Examination of Brain Serotonin Receptors in Patients With Mood Disorders

Multiple lines of evidence suggest that serotonin1A (5-HT1A) receptor and serotonin
transporter (5-HTT) function is abnormal in major depressive disorder (MDD) and that somatic
antidepressant treatments effect changes in the function of these systems that are relevant
to their therapeutic mechanisms. The data supporting these hypotheses have been obtained by
assessing neuroendocrine and temperature responses to 5-HT1A agonists in MDD subjects,
measuring 5-HT1A receptor and 5-HTT binding in brain tissue acquired post mortem from small
samples of MDD subjects, and examining effects on 5-HT1A receptor function in rats following
antidepressant drug (AD) administration. The recent development of highly selective 5-HT1A
receptor and 5-HTT radioligands for positron emission tomography (PET) imaging made direct,
noninvasive exploration of the central serotonin sites binding possible. Two studies
conducted using one of these, [carbonyl-11C]-WAY-100635, found reduced 5-HT1A receptor
binding potential (BP) in the mesiotemporal cortex, the raphe, and the prefrontal cortex
(PFC). Pilot data from these studies suggested that the abnormal reduction in 5-HT1A receptor
BP is more prominent in bipolar disorder (BD) than MDD subjects (i.e., unipolar depressives)
who did not have bipolar relatives, and that it exists independently of mood state.

However, these data have the limitations that the subject samples studied in these
preliminary post mortem and PET series have been small, and that [carbonyl-11C]WAY-100635
uptake is difficult to quantitate in PET images. Therefore, these observations require
replication in subject samples large enough to establish main effects of diagnostic subtype
using a 5-HT1A receptor radioligand that can be validly quantitated. A selective 5-HT1A
receptor radioligand suitable for this purpose, [18F]FC-WAY100635 ([18F]FCWAY), has recently
been developed at the NIH. In addition, a recently developed selective 5-HTT ligand, [11C]
DASB provides a unique opportunity to image the 5-HTT in the same depressed sample.

The proposed study will advance knowledge regarding the neurobiology of mood disorders by
employing PET and [18F]FCWAY and [11C] DASB to compare 5-HT1A receptor BP between mood
disordered and healthy control subjects in the mesiotemporal cortex, raphe, anterior
cingulate gyrus, and left orbital cortex. The following hypotheses, based upon pilot data
acquired using [carbonyl-11C]-WAY-100636, will be tested: 1) Depressives have reduced 5-HT1A
receptor binding relative to healthy controls. 2) Bipolar depressives will have significantly
greater reductions in 5-HT1A receptor binding than unipolar depressives with only unipolar
relatives. A pilot study in which bipolar depressives are treated with lithium or divalproex
and then re-imaged will test the third hypothesis, that 5-HT1A receptor binding will increase
in bipolar subjects during mood stabilizer therapy.

Finally, because central 5-HT1A receptor density is down-regulated in rodents by
corticosterone administration and by stress-mediated corticosterone secretion, assessments of
hypothalamic-pituitary-adrenal (HPA) axis activity (which is commonly elevated in MDD and
BD), will be assessed to determine whether down-regulation of 5-HT1A receptors correlates
with cortisol hypersecretion in mood disorders. Because this down-regulation may play a
compensatory role to reduce cortisol secretion, neuroendocrine assessments of long-standing
rather than acute hypercortisolism and of the pathophysiological diathesis to hypersecrete
cortisol will be emphasized as providing the most sensitive correlates of reduced 5-HT1A
receptor binding. A medical control group with Cushing's Disease will also be imaged to
determine whether pathological elevation of glucocorticoid levels down-regulates 5-HT1A
receptor expression in humans, as it does in rats.

- INCLUSION CRITERIA:

MDD SAMPLES:

Seventy subjects (ages 18 to 60) with MDD will be selected who additionally meet criteria
for one of 3 subgroups:

A) MDD, Currently depressed with FPDD, as defined by DSM-IV criteria for recurrent MDD,
currently in a major depressive episode, who have a first degree relative with MDD but no
first degree relatives with mania, alcoholism, or antisocial personality disorder.

B) MDD, Currently in remission with a history of FPDD, defined as a period of at least six
months with no more than one clinically significant symptom, and during which time subjects
were not taking an AD agent. Subjects will thus meet the historical criteria for recurrent
MDD (DSM-IV). We will also require that subjects previously had a least one antidepressant
drug trial, to ensure that the severity of previous episodes warranted treatment.

C) MDD, Currently depressed, non-FPDD. To assess the specificity of the findings in MDD to
FPDD, a sample meeting criteria for MDD, currently in a depressive episode, but not FPDD
will also be imaged.

BIPOLAR DEPRESSED SAMPLE:

Forty five subjects (ages 18 to 60) who meet DSM-IV criteria for bipolar disorder and are
currently in a major depressive episode. Subjects may be inpatients or outpatients. Because
effective treatment will not be discontinued for the purposes of this protocol, subjects
will be identified who have never been treated or who have discontinued medication due to
lack of efficacy, noncompliance, physician order or other reasons prior to study entry.

HEALTHY, LOW RISK, CONTROL SAMPLE:

One hundred and four subjects (ages 18 to 60) who have not met criteria for any major
psychiatric disorder. The control subjects will have no known first or second degree
relatives with mood disorders.

CUSHINGS DISEASE CONTROL SAMPLE:

Ten subjects (ages 18 to 60) with probable Cushing's Disease will be recruited who have
both clinical and biochemical evidence of hypercortisolism (including urinary free cortisol
excretion higher than the upper limit of normal (greater than 248) nmole/day, and marked
central adiposity, cutaneous atrophy, proximal myopathy, and large purple striae). The
diagnosis of probable Cushing's Disease will also have been established prior to referral
via CRH and ACTH.

MENSTRUALLY-RELATED DYSPHORIC DISORDER SAMPLE:

(n equals 12; ages 18-50). These females are recruited, screened and diagnosed by
collaboration under protocol number 81-M-0126, previously approved by IRB, entitled 'The
Phenomenology and Biophysiology of Menstrually Regulated Mood and Behavioral Disorders',
principal investigator, David Rubinow, M.D. As described in that protocol these subjects
must have a regular menstrual cycle lasting 21 - 33 days and meet the following criteria:
1) history within the last two years of at least six months with menstrually-related mood
or behavioral disturbances of at least moderate severity - that is, disturbances that are
distinct in appearance and associated with a notable degree of subjective distress; 2) a 30
percent increase in mean negative mood ratings (relative to the range of the scale
employed) in the premenstrual week compared with the week following the end of menses in at
least two of the three cycles; 3) age 18 to 50; 4) not pregnant and in good medical health;
5) regular menses.

REMITTED MDD WITH AND WITHOUT A HISTORY OF PPD:

(n=40; ages 18-40). These subjects are recruited, screened and diagnosed by collaboration
under 95-M-0097, previously approved by IRB entitled An Endocrine Modal for Postpartum Mood
Disorders. These subjects will have a history of DSM-IV MDD. Twenty will also have had a
hypomanic/manic episode that occurred within three months of childbirth and twenty will
have not had the latter within three months of childbirth. Women will have been well for a
minimum of one year, have a regular menstrual cycle for at least three months, medication
free (including birth control pill), have no history of puerperal suicide attempts or
psychotic episodes requiring hospitalization. Any women with a current axis I psychiatric
diagnosis will be excluded from participating in this protocol.

HEALTHY FEMALE CONTROLS UNDER 95-M-0097:

(n=20, age 18-40). These healthy control women are under an identical drug administration
regimen as the 40 remitted MDD women above and will similarly be recruited and screened
under 95-M-0097. They will meet the same criteria specified for the remitted MDD group
above but will not have any past or present Axis I diagnosis or evidence of menstrually
related mood disorders. This healthy sample of females will have given birth.

EXCLUSION CRITERIA:

Subjects must not have taken antidepressant or other medications likely to alter monoamine
neurochemistry or cerebrovascular function for at least 3 weeks (8 weeks for fluoxetine)
prior to scanning. Subjects being scanned at two points or the same point twice in their
menstrual cycle must not have taken birth control pills for at least 6 months prior to
scanning. However, effective medications will not be discontinued for the purposes of this
study. Instead, subjects will be recruited who are not currently receiving psychotropic
drugs. Subjects will also be excluded if they have:

1. serious suicidal ideation or behavior;

2. psychosis to the extent that the ability to provide informed consent is in doubt;

3. medical or neurological illnesses likely to affect physiology or anatomy;

4. a history of drug or alcohol abuse within 1 year or a lifetime history of alcohol or
drug dependence (DSM IV criteria);

5. current pregnancy

6. current breast feeding;

7. general MRI exclusion criteria;

8. previous exposure to ecstasy (i.e. MDMA) which has neurotoxic effects on 5-HTT
expressing neurons.

Subjects beyond age 50 are excluded from the MRMD sample due to peri-menopausal status and
subjects beyond age 60 are excluded to reduce the biological heterogeneity encompassed by
the MDD criteria, since depressives whose age-at MDD-onset is later than 60 have a far
greater likelihood of having MRI correlates of cerebrovascular disease than age-matched,
healthy controls or age-matched, early-onset depressives.

Subjects whose first major depressive episodes arose temporally after other major medical
or psychiatric conditions will also be excluded, since their functional imaging results
generally differ from those reported in primary MDD.