Vincent Van Gogh's 1890 painting, "On the Threshold of Eternity," well depicts depression. With its blue tones and the figure of a despondent old man so doubled over in his chair that his face isn't visible, it shows how lonely and alone a depressed person can feel. Van Gogh himself suffered from depression, and committed suicide before the end of that year. But depression - which affects between 10% and 20% of any population at some time during their lives - has many faces. There are several types, numerous causes and different forms. Unipolar depression (also known as clinical depression, major depression and severe depression) is the most common type, and among all medical illnesses is one of the leading cause of disability in the US and other Western countries. Routine functions such as eating, sleeping and even getting out of bed in the morning are difficult for patients suffering from unipolar depression, which occurs in any ethnic, racial or socioeconomic group, hits women more frequently than men, and can affect even children. It can be a one-time phenomenon that never recurs, but the majority of those diagnosed will have at least one more occurrence. Bipolar depression, also known as bipolar affective disorder and previously referred to as manic depression, typically begins in teenagers or young adults, and affects only about 10% as many people as unipolar depression - but it can be even more devastating. In this condition, patients present alternating cycles of abnormal behavior, sometimes depressive and sometimes manic. They may swing from highs to lows several times a year. Still, a considerable number, especially those with a family that ensures they take their medication, are able to live productive lives. PROF. ROBERT HAIM BELMAKER, Ben-Gurion University of the Negev's Hoffer-Vickar Professor of Psychiatry, was in the unusual position of being commissioned by the prestigious New England Journal of Medicine (NEJM) to write review articles on bipolar disorder (in 2004) and now another on major depressive disorder and the biological mechanisms behind it. Belmaker, born in Los Angeles in 1947, is known worldwide as an Israeli pioneer in biological psychiatry. At the age of 20, he met and married his wife Elaine (today Dr. Ilana Belmaker, the Health Ministry's southern district health officer and expert in preventive medicine) and graduated from Harvard. Today, living in Omer, they have six children aged 23 to 35, none of whom became a physician. However, the eldest is a paleontologist, the next a coral reef scientist, the third is doing his doctorate in geology, the fourth is studying animal behavior, the fifth is supervising local authority budgets in the Interior Ministry, and the youngest is a journalism student. Belmaker told The Jerusalem Post that he wanted to become a psychiatrist since the age of 10. "My parents wanted me to be a doctor, but I was interested in the mind-body problem, so the perfect solution was psychiatry. As a part of the 1960s college generation in the States, I was deeply concerned about social justice and health care availability. I remember believing that offering truly inexpensive psychotherapy would be a major career goal." He earned his M.D. degree from Duke University in 1971, where he spent a year researching autonomic psychophysiology and was first exposed to "the excitement of scientific controversy." BELMAKER continued his medical education at Duke with a residency in psychiatry in the early 1970s, and was influenced by Prof. Elliot Gershon's review of the genetics of bipolar illness. A turning point in his career arrived in 1973, when he contacted Gershon, who was then director of research at the Jerusalem Mental Health Center-Ezrath Nashim, and who had introduced the use of lithium for treating bipolar affective disorder in Israel. Gershon moved to Washington, DC to distinguish himself in psychiatric genetic research. The following year, at the age of 27, Robert Belmaker was named Gershon's successor and was also a lecturer and later associate professor of psychiatry at the Hadassah-Hebrew University School of Medicine. Working with neurochemist Prof. Richard Ebstein, Belmaker found that lithium could block adrenalin-induced rises in a substance called plasma cyclic AMP in bipolar patients, and their joint research was published in Nature. But after more than a decade in Jerusalem, the Belmaker family went to Beersheba, where he became director of acute psychiatry at the Beersheba Mental Health Center and associate professor of psychiatry at BGU's medical school, and Ilana became a senior Health Ministry official. Summing up his psychiatrist career, Belmaker said: "I believe I have contributed to an enterprise whereby lithium will soon join other families of psychoactive compounds in having a defined mechanism of action, thereby allowing the synthesis of a group of lithium-like compounds for human use in collaboration with the pharmaceutical industry." He is also widely credited as a founder of the field of transcranial magnetic stimulation for psychiatric treatment, and was the first to publish a paper (again in Nature) on the molecular genetics of personality, opening up yet another field of study. "Ebstein and I have worked for years on lithium, particularly on how it works, and we have been looking for safer and synthetic alternatives." Last year, Belmaker was elected president of the International College of Neuropsychopharmacology, a rare honor for an Israeli. "The main message of my just-published NEJM article is that clinical depression is much more heterogeneous than we thought. A decade ago, psychiatry researchers would describe a patient with acute unipolar depression who recovers after getting medication as 'textbook depression.' Now we know it usually recurs, sometimes in chronic form. There are also people with a kind that appears out of the blue, and after they get treatment, usually with medication, it never recurs. Then there are people who had a fine childhood with no trauma but suddenly get depressed despite having no psychological reason for it. There are patients with an anxious and depressive personality; those who suffered post-childhood trauma and suffer from depression all their lives; and elderly people who due to endothelial blockages in the blood vessels to the brain have vascular depression," Belmaker explained. "THE SECOND message of my article is that we need to be skeptical of each new theory that comes along, as none seems to explain everything. Neurotransmitters are widely blamed for depression, and there are new psychotropic drugs all the time, but none of the medicines works better or less well than their predecessors. There is the cortisol theory that explains post-traumatic stress, but they do not explain depression that comes out the blue. "Most 'facts' that psychiatrists think they know, we don't really know. Patients push us into giving simple answers, and we have to persuade them to take medications. But we certainly haven't measured the effects of the medications. Researchers with certain theories are actually impeding further progress in treating depressive patients. So it was an honor to be asked by the NEJM to write my article, as it provided a forum to give our field a little 'slap in the face.' If you start believing your own theory, you are no longer objective." Bipolar depression can appear in a sporadic or genetic form. About 50% of bipolar patients have no family history, he said. "No single bipolar gene has been identified, and apparently there is not one but several that interact with environmental factors." He noted that oncologists and urologists differ on the meaning of prostate-specific antigen tests as an indicator of prostate cancer. "And that's a physical disease. Think how much more complicated are psychiatric disorders." IN 2006, Belmaker and colleagues published a study on treating depression in children with omega-3 fatty acids, which are found in fish oil capsules. Depression is an increasingly common problem that affects an estimated 2% to 4% of children in Western countries. Such youngsters are at higher risk of substance abuse and suicide. Most depressed children have been treated with a class of drugs known as selective serotonin-reuptake inhibitors (SSRIs), but over a fifth of the young patients experience side effects such as agitation and sleep disturbances from these drugs, and their use has also been linked to an increased risk of suicidal thoughts and suicide attempts. In Belmaker's study, 20 children aged six to 12 were randomly assigned to receive omega-3 capsules or a placebo daily for 16 weeks. After treatment, the depression improved by more than 50% in seven of the 10 children receiving omega-3, and disappeared completely in four of them, while none of the 10 children who got the placebo showed much improvement. "This is the first study to demonstrate a beneficial effect of omega-3 fatty acids as a treatment for depression in young children," said Belmaker. It was not clear how fatty acids work to relieve depression, but the authors suggested that the effect is probably due mainly to EPA (eicosapentaenoic acid) and not the DHA (docosahexaenoic acid) component. "Considering the potential adverse side effects of commonly used antidepressant drugs," said Belmaker, "omega-3 fatty acids look like an attractive alternative for children with depression." ALTHOUGH HE was asked by NEJM to concentrate on the biological origins of clinical depression, Belmaker stressed in the interview that biology is certainly not the only factor in mental illness, and taking medications is not the only way to treat it. "Different sub-types of depression have different psychological and biological components. Antidepressant drugs may not help people who suffered trauma in childhood. Cognitive behavioral therapy may help some patients, but they may not be verbal enough to benefit, so medication could be preferable. There is much evidence that parental divorce is important in creating a predisposition for depression in some cases, but the subject is avoided as being too 'politically incorrect' to discuss in our society, which increasingly regards divorce as a normative thing." Psychoanalysis can help many patients, he continued. "Sigmund Freud was not wrong; his work has a lot of truth in it. But it was often misinterpreted and became untested ideology. Not every problem comes from childhood experience, and psychotherapy doesn't always have to take years." In his bipolar clinic every Monday, he works with Dr. Yemima Osher, a psychotherapist. "We see all patients together, and if he or she needs brief or longer supportive psychotherapy, she sees them again," said Belmaker, who spends the rest of his time in the neurochemistry lab with Prof. Glila Agam (co-author of the latest NEJM article), doing administrative work as assistant director of the Beersheba Mental Health Center and at BGU's medical school.