What does the word "depression" bring to mind? A slump in theeconomy? A mood of persistent sadness? Or both of the above?

Job loss ranks third among the five commonest stressors causingpsychotic depression, as discerned by a leading psychiatrist in thefield. He is Kenneth Kendler, at the Virginia CommonwealthUniversity's Medical College.

"The largest of the slings and arrows we all confront," Kendler toldBioWorld Today, "is death of a relative; the second, maritaldifficulties; the fourth a major health problem; the fifth, financialdifficulties."

Statistics of clinical depression's incidence and prevalence in thepopulation are problematic because the very definition of the disorderis far from fixed. Kendler said a lifetime prevalence of 17 percent isvalid _ afflicting about one in five Americans and Europeans duringtheir lifetimes. Psychiatrists call the depressive state unipolardepression.

"In any six-month period," according to the American PsychiatricAssociation (APA), "9.4 million Americans suffer from this disease.One in four women and one in 10 men can expect to develop itduring their lifetime."

Depressed people, the APA fact-sheet (as cited by the NationalAlliance for Research on Schizophrenia and Depression in GreatNeck, N.Y.) states, "have pervasive feelings of sadness, helplessness,hopelessness, worthlessness and irritability. Some people are sodisabled by feelings of despair that they cannot even build up theenergy to call a doctor."

Churchill's `Black Dog' _ Kaiser's Manic Moments

Among historical figures believed to have suffered from unipolardepression, Kendler mentioned Abraham Lincoln and WinstonChurchill. But he noted that their diagnoses are speculative "becausethey were not examined by psychiatrists." Churchill, he recalled,"talked about his `black dog,' _ severe bouts of melancholia."

Germany's Kaiser Wilhelm II, of World War I fame, is thought tohave had not unipolar but bipolar illness. That is, his melancholiaalternated with episodes of mania.

Some years ago, Kendler worked in the psychiatric emergency roomof a hospital that serviced the Los Angeles International Airport. "Acouple of times a week," he remembered, "a manic patient would flyin on an airplane, loudly demanding to see his press agent, andraising a ruckus over the whereabouts of his $5 million Hollywoodcontract. The police would pick him up and bring him to our ER."

He observed that "Depressives, aside from a suicide attempt, arefairly quiet. Manics are a little harder to ignore."

Kendler has conducted a recent twin study, which suggests thatapproximately 40 percent of the risk in major depression is genetic.

The APA document states that "Close relatives of people sufferingfrom bipolar illness are 10 to 20 times more likely than the generalpopulation to develop either depression or manic-depressive illness."

A research report in this week's The Lancet (dated March 16, 1996,)unravels one strand in the complex tapestry of depression's geneticcomponent. It bears the title: "Polymorphism in serotonin transportergene associated with susceptibility to major depression." GuyGoodwin, a professor of psychiatry at the University of Edinburgh,Scotland, is the paper's senior author.

Antidepressants Target Serotonin's Action Site

Serotonin's role in psychosis, Goodwin told BioWorld Today, goesback to "a pharmacologist called Julius Axelrod, who was awarded aNobel prize in 1970 for discovering the mechanism whereby theactions of transmitters like serotonin were terminated in the brain."

Describing the serotonin re-uptake site protein, he explained: "Theserotonin transporter selectively transports serotonin back across themembrane at the neuronal synaptic site." What was left of thehormone after it had acted "was hoovered up and transported backinto the cell terminal, thus limiting its duration of action."

"That mechanism," he added, "is the primary, unique and unknownpharmacological site of action targeted by the modern antidepressantdrugs, such as Prozac."

The human serotonin transporter gene sits on chromosome 17's longarm. Goodwin's experiment, described in The Lancet, aimed todetect a genetic link between variations (alleles) of that gene'spaternal and maternal inheritance and the occurrence of depressivedisorder.

He and his co-authors compared the serotonin transporter genes of 83patients _ 39 unipolar, 44 bipolar _ with 193 controls, 122 blooddonors, 71 volunteers screened for psychiatric disorders.

They found three variant alleles, containing nine, 10 and 12 copies ofa 17-base-pair DNA segment. The nine-copy variant correlatedsignificantly with risk of unipolar disorder.

"The normal healthy individual," Goodwin said, "varies just as doesthe not-so-healthy patient with major depression.

"Most people in the normal population," he went on, "have 10s and12s. And we don't have clear evidence that possession of anythingother than a nine has implications for major depression."

At the clinical level, the Edinburgh group's work continues, first torepeat its findings in a larger, more statistically valid cohort ofpatients and controls. Second, to confirm "whether people with ninerepeats had a better or worse prognosis, or responded better to onetreatment or another. That data," Goodwin concluded, "would beextremely useful for clinicians who are treating patients fordepression." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.