INCLUSION CRITERIA
rMDD Sample: eighty subjects (ages 18-50) with rMDD will be selected, 20 s allele carriers and 20 l/l homozygotes. Remission is defined as a period of at least three months during which the subject has not taken an antidepressant agent (Frank et al. 1991), with Hamilton Depression Rating Scales (HDRS; 21-item) (Hamilton 1960) scores in the non-depressed range (less than 8), and with no more than one clinically significant depressive symptom. Subjects will be assessed for past psychiatric disorders using the Structured Interview for DSM IV (SCID) (Spitzer et al. 1992).
Healthy Control Sample: eighty healthy subjects (ages 18-50) without a known personal or family history of psychiatric disorders in first-degree relatives will be selected, 20 s allele carriers and 20 l/l homozygotes.
Since the s and l alleles occur with differing frequencies in different populations, it is important to control for the potential confound of population stratification. For example, the l allele occurs with 80% frequency in populations of African ancestry, while the s allele occurs with 70% frequency in populations of East Asian origin. Therefore if ethnicity is not controlled for, any association of mood response to TD with a particular allele could potentially be due to other differences between ethnicities.
In order to counteract this issue in the present study, we intend for the first 20 rMDD subjects and first 20 controls to be Caucasian. At this stage, behavioral and neural differences between the genetic sub-groups in response to TD will be analyzed. If any statistically significant differences are apparent between the genetic sub-groups, a further 20 rMDD subjects and 20 controls will be recruited who are not Caucasian, 10 l/l homozygotes and 10 s allele carriers in each group. These ethnically mixed genetic sub-groups will then be compared to the equivalent Caucasian genetic sub-groups in a final analysis to determine whether the effect of the 5-HTTLPR polymorphism on response to TD occurs independent of ethnic origin.
EXCLUSION CRITERIA
Subjects must not have taken antidepressant drugs for at least 3 months (4 months for fluoxetine) prior to the fMRI studies or other medications likely to alter monoamine neurochemistry or cerebrovascular and cardiovascular function for at least 3 weeks prior to imaging. However, effective medications will not be discontinued for the purposes of this study. Subjects will also be excluded if they have:
1. Psychosis
2. Medical or neurological illnesses likely to affect physiology or anatomy, i.e. hypertension, cardiovascular disorders
3. A history of drug (including benzodiazepines (BZD)) or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria)
4. Current pregnancy (as documented by pregnancy testing at screening or at days of the challenge studies)
5. Current breast feeding
6. Are smokers
7. Serious suicidal ideation or behavior. In this study, there is a small risk of transient depressive symptoms occurring after ingesting the amino acid mixture. Therefore, if volunteers manifest evidence of serious suicidal ideation or behavior, they will be excluded from participating. Criteria for meeting suicidal ideation include but are not limited to: 1) thoughts of suicide within the past 3 months which are accompanied by intent to harm oneself, serious consideration of means or plan to attempt suicide, evidence of arranging for a suicide attempt (e.g. giving away prized possessions or updating a will), or clear desire to commit suicide, 2) severity of past suicide events, if applicable or 3) a current plan for harming themselves. All assessments will be conducted by an experienced, NIMH credentialed health professional, such as a psychiatrist or psychiatric nurse who will use their expert knowledge and experiences in determining the authenticity of a participant's information and handle the situation accordingly.
GENERAL MRI EXCLUSION CRITERIA:
Subjects must exhibit no or only moderate alcohol use. Subjects with current or previous regular use (greater than 4 weeks) of BZDs and excessive use of alcohol (greater than 8 ounces/day for men and greater than 6 ounces/day for women) in the past or present are ineligible for participation, as such drug use may confound the results (Primus and Gallager 1992; Ulrichsen et al. 1996). Smokers (regular use within the last 3 months) are ineligible because of the evidence for interactions between nicotine and depression (Ong and Walsh 2001), and the possibility of withdrawal symptoms that may affect behavioral and neural responses to TD.
Subjects beyond age 50 are excluded to address the biological heterogeneity encompassed by the MDD criteria, since depressives whose age-at-onset is later than 50 have a far greater likelihood of having MRI correlates of cerebrovascular disease than age-matched healthy controls or age-matched early-onset depressives (Krishnan et al. 1993). Subjects whose first major depressive episodes arose temporally after other medical or psychiatric conditions will also be excluded, since their functional imaging results generally differ from those reported in primary MDD (Drevets 2000).
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 09/17/2008