This chapter provides specific consideration to the problem of a pseudo-treatment-resistant depression (TRD), where a medical condition is misdiagnosed as major depression and so does not respond to antidepressant treatment. Amongst medical causes of depression the most frequent appear to be endocrine, in particular thyroid. The chapter presents the evidence supporting a more direct link between many neurological disorders and major depression. The background prevalence rate of major depression is already high in two groups of patients at risk for HIV infection, namely homosexual men and intravenous drug users. Psychiatrists and other mental health professionals can make an indispensable contribution by raising awareness amongst their colleagues of the importance and frequent neglect of major depression in many common medical disorders ranging from stroke to coronary artery disease. In these situations better recognition and treatment of major depression can only but make a valuable contribution to enhancing patient care.